RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistance (The RESTORE Study) (Restore)

• ClinicalTrials.gov Identifier: NCT02090114
• Recruitment Status: Completed
• First Posted: March 18, 2014
• Results First Posted: June 27, 2022
• Last Update Posted: June 27, 2022
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Prostate Cancer
• Interventions: Drug: Testosterone cypionate; Drug: Testosterone Enanthate; Drug: Abiraterone acetate; Drug: Enzalutamide
• Enrollment: 112

Participant Flow

Recruitment Details
Pre-assignment Details	16 patients failed screen.

Arm/Group Title	Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description	Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Period Title: Overall Study
Started	30	29	29	8
Completed	0	0	0	0
Not Completed	30	29	29	8
Reason Not Completed
Withdrawal by Subject	3	6	2	1
Physician Decision	5	0	1	1
Adverse Event	1	2	2	0
Progressive Disease	20	21	23	6
Death	1	0	1	0

Baseline Characteristics

Arm/Group Title		Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation	Total
Arm/Group Description		Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Total of all reporting groups
Overall Number of Baseline Participants		30	29	29	8	96
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	30 participants	29 participants	29 participants	8 participants	96 participants
		74; (50 to 89)	71; (49 to 85)	69; (41 to 84)	73; (56 to 89)	72; (41 to 89)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants	29 participants	29 participants	8 participants	96 participants
	Female	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Male	30 100.0%	29 100.0%	29 100.0%	8 100.0%	96 100.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants	29 participants	29 participants	8 participants	96 participants
	Hispanic or Latino	0 0.0%	0 0.0%	1 3.4%	1 12.5%	2 2.1%
	Not Hispanic or Latino	24 80.0%	26 89.7%	24 82.8%	7 87.5%	81 84.4%
	Unknown or Not Reported	6 20.0%	3 10.3%	4 13.8%	0 0.0%	13 13.5%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	30 participants	29 participants	29 participants	8 participants	96 participants
White		27 90.0%	26 89.7%	23 79.3%	7 87.5%	83 86.5%
Non-white		3 10.0%	3 10.3%	6 20.7%	1 12.5%	13 13.5%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	30 participants	29 participants	29 participants	8 participants	96 participants
		30 100.0%	29 100.0%	29 100.0%	8 100.0%	96 100.0%

Outcome Measures

1. Primary Outcome

Title	Prostate Specific Antigen (PSA) Response to Bipolar Androgen Therapy (BAT)
Description	Number of participants with ≥50% PSA reduction from pre-BAT baseline level
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

Only 7/8 patients were evaluable from Cohort D.

Arm/Group Title	Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:	Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed	30	29	29	7
Measure Type: Count of Participants; Unit of Measure: Participants
	9 30.0%	5 17.2%	4 13.8%	2 28.6%

2. Primary Outcome

Title	PSA Response to Enzalutamide or Abiraterone Acetate Post Bipolar Androgen Therapy
Description	Number of participants with ≥50% PSA reduction after enzalutamide or abiraterone acetate post-BAT from baseline
Time Frame	up to 24 months

Outcome Measure Data

Analysis Population Description

This outcome measure only applies to cohort A,B, and D. Only 22/30 (Cohort A), 19/29 (Cohort B) and 7/8 (Cohort D) patients had evaluable data.

Arm/Group Title	Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:	Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed	22	19	0	7
Measure Type: Count of Participants; Unit of Measure: Participants
	15 68.2%	3 15.8%		2 28.6%

3. Secondary Outcome

Title	PSA Progression on Enzalutamide or Abiraterone Acetate or Castrate Levels Post-BAT
Description	Time to PSA progression on enzalutamide or abiraterone acetate or return to castrate levels of testosterone post-BAT, defined as the time from the date of re-initiation of enzalutamide or abiraterone acetate or castration-only therapy to the date of the PSA measurement when it shows an increase by ≥25% above the nadir value that occurred following re-initiation of enzalutamide or abiraterone acetate or castration-only therapy and confirmed by a repeat PSA 4 weeks later (PCWG2).
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

Only 21/30 participants were evaluable from Cohort A. Only 19/29 participants were evaluable from Cohort B.This outcome measure does not apply to Cohort D.

Arm/Group Title	Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:	Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed	21	19	29	0
Median (95% Confidence Interval); Unit of Measure: months
	5.5 [1]; (4.6 to NA)	3.7; (1.5 to 5)	NA [1]; (NA to NA)

[1]

insufficient number of participants with events

4. Secondary Outcome

Title	PSA Progression on BAT (Bipolar Androgen Therapy )
Description	Time to PSA progression on BAT. Time to PSA progression on BAT is defined as the time from the date of initial dose of Testosterone to the date of the PSA measurement when it shows an ≥25% increase above the nadir value and confirmed by a repeat PSA 4 weeks later (PCWG2 criteria) during the treatment with BAT.
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:	Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed	30	29	29	7
Median (95% Confidence Interval); Unit of Measure: months
	3.3; (2.7 to 5.5)	3.2; (2.5 to 6)	0.93; (0.93 to 5.58)	3 [1]; (2.8 to NA)

[1]

insufficient number of participants with events

5. Secondary Outcome

Title	Disease Response as Defined by RECIST 1.1 (Soft Tissue Lesions) and PCWG2 Criteria (Bone Lesions)
Description	Number of participants with complete or partial response post-BAT as defined by RECIST 1.1 (for soft tissue lesions) and PCWG2 criteria (for bone disease), or return to castration-only post-BAT.
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

12/30 participants from Cohort A, 7/29 participants from Cohort B, 13/20 from Cohort C, and 7/8 participants from Cohort D were evaluable for this outcome measure.

Arm/Group Title	Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:	Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed	12	7	13	7
Measure Type: Count of Participants; Unit of Measure: Participants
	6 50.0%	2 28.6%	4 30.8%	0 0.0%

6. Secondary Outcome

Title	Initiation of Docetaxel Chemotherapy
Description	Time to initiation of docetaxel chemotherapy
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

Data was not collected to assess this outcome measure.

Arm/Group Title	Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:	Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed	0	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

7. Secondary Outcome

Title	Quality of Life (QoL) as Assessed by FACIT-F Score
Description	Functional Assessment of Chronic Illness Therapy, Fatigue Subscale (FACIT-F) assesses Fatigue with a total score range of 0-52, with a higher score reflecting better QoL.
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

25/30 participants in Cohort A, 22/29 participants in Cohort B, 28/29 participants in Cohort C were evaluable for this outcome measure. Data was not collected from participants for Cohort D.

Arm/Group Title		Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:		Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed		25	29	29	0
Mean (Standard Deviation); Unit of Measure: score on a scale
Baseline	Number Analyzed	25 participants	22 participants	28 participants	0 participants
		13.28 (6.73)	16.86 (7.62)	13 (5.57)
Cycle 1 Day 85	Number Analyzed	25 participants	29 participants	29 participants	0 participants
		10.64 (5.51)	13.85 (7.42)	11.55 (3.39)

8. Secondary Outcome

Title	Safety and Tolerability as Assessed by Number of Participants With Adverse Events
Description	Number of participants who experience adverse events, as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

In cohort D, data was only collected from 7/8 participants.

Arm/Group Title	Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:	Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed	30	29	29	7
Measure Type: Count of Participants; Unit of Measure: Participants
	30 100.0%	29 100.0%	29 100.0%	7 100.0%

9. Secondary Outcome

Title	Quality of Life (QoL) as Assessed by RANDSF-36
Description	RAND 36-Item Short Form (RANDSF-36) assesses physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, general health perceptions, and perceived change in health with a total score range of 0-100. The total score from all of the questions answered is divided by the total number of the questions answered yielding a global score from 0-100, with a higher score reflecting a better QoL.
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

25/30 participants in Cohort A, 19/29 participants in Cohort B, 25/29 participants in Cohort C were evaluable for this outcome measure. Data was not collected from participants in Cohort D.

Arm/Group Title		Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:		Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed		30	29	29	0
Mean (Standard Deviation); Unit of Measure: score on a scale
Baseline	Number Analyzed	25 participants	19 participants	25 participants	0 participants
		72.23 (18.89)	64.36 (18.70)	69.72 (17.72)
Cycle 1 Day 85	Number Analyzed	30 participants	29 participants	29 participants	0 participants
		71.76 (19.20)	73.97 (19.96)	73.40 (17.98)

10. Secondary Outcome

Title	Quality of Life (QoL) as Assessed by BPI
Description	Brief Pain Inventory (BPI) assesses the severity of pain and its impact on functioning with scales ranging from 0-10, with a higher score indicating a higher level of pain.
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

Data was not collected for this outcome measure.

Arm/Group Title	Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:	Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed	0	0	0	0

No data displayed because Outcome Measure has zero total analyzed.

11. Secondary Outcome

Title	Quality of Life (QoL) as Assessed by IIEF
Description	International Index of Erectile Function (IIEF-5) is a diagnostic tool for erectile dysfunction, with a total score range of 5-25, with the lowest score indicating a higher degree of dysfunction.
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

20/30 participants in Cohort A, 21/29 participants in Cohort B, 25/29 participants in Cohort C were evaluable for this outcome measure. Data was not collected from participants in Cohort D.

Arm/Group Title	Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:	Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed	30	29	29	0
Mean (Standard Deviation); Unit of Measure: score on a scale
Baseline	8 (3.57)	7.33 (3.89)	12.56 (12.86)
BAT C1D85	24.13 (21.63)	24.94 (19.71)	22.44 (15.53)

12. Secondary Outcome

Title	Quality of Life (QoL) as Assessed by PANAS
Description	Positive and Negative Affect Schedule (PANAS) is a self-report measure that is made up of two mood scales, one measuring positive affect and the other measuring negative affect, with a total score range from 10-50 with a higher score on the positive scale indicating greater levels of positive affect and a lower score on the negative scale indicating less of a negative affect.
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

20/30 participants in Cohort A, 18/29 participants in Cohort B, 25/29 participants in Cohort C were evaluable for this outcome measure. Data was not collected for Cohort D.

Arm/Group Title		Cohort A:Post-enzalutamide	Cohort B: Post-abiraterone	Cohort C: Castration Only	Cohort D: Mutation
Arm/Group Description:		Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.	Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.	Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.	Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
Overall Number of Participants Analyzed		30	29	29	0
Mean (Standard Deviation); Unit of Measure: score on a scale
Baseline	Number Analyzed	20 participants	18 participants	25 participants	0 participants
		46.15 (10.55)	48 (11.47)	41.24 (14.35)
BAT C1D85	Number Analyzed	30 participants	29 participants	29 participants	0 participants
		45.1 (9.09)	45.22 (12.94)	44.48 (11.06)

Adverse Events

Time Frame	Up to 2 years
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Cohort A:Post-enzalutamide		Cohort B: Post-abiraterone		Cohort C: Castration Only		Cohort D: Mutation
Arm/Group Description	Men with castration-resistant prostate cancer who have progressed on enzalutamide will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with enzalutamide 160 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Enzalutamide: XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.		Men with castration-resistant prostate cancer who have progressed on abiraterone will be enrolled to this cohort. These patients will then receive intramuscular injections with testosterone cypionate 400 mg every 28 days or testosterone enanthate 400 mg every 28 days. Upon progression on testosterone cypionate or enanthate, men will be retreated with abiraterone 1000 mg by mouth daily. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days. Abiraterone acetate: Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.		Men with metastatic prostate cancer who have only received first line hormone therapy with LHRH agonist alone or LHRH agonist plus an anti-androgen. Patients who have developed castrate resistance to first line therapy and have then received second line hormone therapy of any kind (including flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, enzalutamide, ARN-509 and investigational anti-androgens) are not eligible for enrollment in this cohort. Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.		Men with metastatic prostate cancer who have castrate resistant prostate cancer with inactivating somatic or germline mutations in the genes TP53, RB1 or PTEN identified using clinical grade sequencing of tumor tissue performed by qualified laboratory. Patients must have mutations in ≥2 of these genes to be eligible. Eligible patients must have progressed on first line hormone therapy with LHRH agonist alone and must have received at least one but not more than two second generation androgen ablative therapy (i.e. Abiraterone, Enzalutamide or Apalutamide). Testosterone cypionate: DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate and will be administered at 400mg IM every 28 days. Testosterone Enanthate: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative. Will be administered at 400mg IM every 28 days.
All-Cause Mortality
	Cohort A:Post-enzalutamide		Cohort B: Post-abiraterone		Cohort C: Castration Only		Cohort D: Mutation
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	1/30 (3.33%)		0/29 (0.00%)		1/29 (3.45%)		0/8 (0.00%)
Serious Adverse Events
	Cohort A:Post-enzalutamide		Cohort B: Post-abiraterone		Cohort C: Castration Only		Cohort D: Mutation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/30 (10.00%)		4/29 (13.79%)		5/29 (17.24%)		1/8 (12.50%)
Blood and lymphatic system disorders
disseminated intravascular coagulation *	0/30 (0.00%)	0	1/29 (3.45%)	1	0/29 (0.00%)	0	0/8 (0.00%)	0
Cardiac disorders
myocardial infarction *	1/30 (3.33%)	1	0/29 (0.00%)	0	1/29 (3.45%)	1	0/8 (0.00%)	0
Cardiac Arrest *	0/30 (0.00%)	0	0/29 (0.00%)	0	1/29 (3.45%)	1	0/8 (0.00%)	0
Gastrointestinal disorders
Lower gastrointestinal hemorrhage *	0/30 (0.00%)	0	0/29 (0.00%)	0	1/29 (3.45%)	1	0/8 (0.00%)	0
Infections and infestations
Urinary Tract Infection *	0/30 (0.00%)	0	0/29 (0.00%)	0	0/29 (0.00%)	0	1/8 (12.50%)	1
Metabolism and nutrition disorders
Pancreatitis, elevated lipase, amylase *	1/30 (3.33%)	1	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Nervous system disorders
Neurological Symptoms *	0/30 (0.00%)	0	1/29 (3.45%)	1	0/29 (0.00%)	0	0/8 (0.00%)	0
stroke *	0/30 (0.00%)	0	0/29 (0.00%)	0	1/29 (3.45%)	1	0/8 (0.00%)	0
Renal and urinary disorders
Urine Retention *	0/30 (0.00%)	0	1/29 (3.45%)	1	0/29 (0.00%)	0	0/8 (0.00%)	0
Acute Renal Insufficiency *	1/30 (3.33%)	1	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia *	0/30 (0.00%)	0	1/29 (3.45%)	1	0/29 (0.00%)	0	0/8 (0.00%)	0
dyspnea *	0/30 (0.00%)	0	0/29 (0.00%)	0	1/29 (3.45%)	1	0/8 (0.00%)	0
* Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Cohort A:Post-enzalutamide		Cohort B: Post-abiraterone		Cohort C: Castration Only		Cohort D: Mutation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/30 (100.00%)		29/29 (100.00%)		29/29 (100.00%)		8/8 (100.00%)
Blood and lymphatic system disorders
Increased Hemoglobin *	11/30 (36.67%)	11	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Anemia *	5/30 (16.67%)	16	7/29 (24.14%)	10	0/29 (0.00%)	0	2/8 (25.00%)	2
polycythemia *	0/30 (0.00%)	0	0/29 (0.00%)	0	1/29 (3.45%)	1	0/8 (0.00%)	0
Elevated hematocrit *	1/30 (3.33%)	1	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Eye disorders
eye discorder *	3/30 (10.00%)	3	1/29 (3.45%)	1	0/29 (0.00%)	0	0/8 (0.00%)	0
Gastrointestinal disorders
nausea *	7/30 (23.33%)	9	4/29 (13.79%)	4	1/29 (3.45%)	1	1/8 (12.50%)	1
abdominal pain *	3/30 (10.00%)	3	1/29 (3.45%)	1	3/29 (10.34%)	3	0/8 (0.00%)	0
bowel obstruction *	0/30 (0.00%)	0	1/29 (3.45%)	1	1/29 (3.45%)	1	0/8 (0.00%)	0
diarrhea *	1/30 (3.33%)	1	0/29 (0.00%)	0	3/29 (10.34%)	3	1/8 (12.50%)	1
constipation *	3/30 (10.00%)	3	3/29 (10.34%)	4	1/29 (3.45%)	1	1/8 (12.50%)	2
bloating *	0/30 (0.00%)	0	0/29 (0.00%)	0	0/29 (0.00%)	0	1/8 (12.50%)	1
General disorders
fatigue *	17/30 (56.67%)	23	5/29 (17.24%)	5	5/29 (17.24%)	5	0/8 (0.00%)	0
edema *	4/30 (13.33%)	5	8/29 (27.59%)	12	7/29 (24.14%)	8	1/8 (12.50%)	3
fever *	1/30 (3.33%)	1	2/29 (6.90%)	2	0/29 (0.00%)	0	1/8 (12.50%)	1
chest pain *	2/30 (6.67%)	2	2/29 (6.90%)	2	2/29 (6.90%)	2	0/8 (0.00%)	0
cold symptoms *	2/30 (6.67%)	2	0/29 (0.00%)	0	2/29 (6.90%)	2	0/8 (0.00%)	0
Hepatobiliary disorders
gallstone *	1/30 (3.33%)	1	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Infections and infestations
sinusitis *	3/30 (10.00%)	4	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Injury, poisoning and procedural complications
fall *	3/30 (10.00%)	3	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Investigations
elevated ALK Phos *	0/30 (0.00%)	0	3/29 (10.34%)	3	0/29 (0.00%)	0	0/8 (0.00%)	0
weight loss *	4/30 (13.33%)	4	3/29 (10.34%)	3	0/29 (0.00%)	0	0/8 (0.00%)	0
Creatinine Increased *	3/30 (10.00%)	4	1/29 (3.45%)	1	1/29 (3.45%)	2	1/8 (12.50%)	1
High cholesterol *	3/30 (10.00%)	3	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Elevated liver enzymes *	1/30 (3.33%)	1	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Elevated AST *	0/30 (0.00%)	0	1/29 (3.45%)	1	0/29 (0.00%)	0	0/8 (0.00%)	0
Elevated troponin *	0/30 (0.00%)	0	0/29 (0.00%)	0	1/29 (3.45%)	1	0/8 (0.00%)	0
Metabolism and nutrition disorders
anorexia *	3/30 (10.00%)	3	5/29 (17.24%)	7	1/29 (3.45%)	1	1/8 (12.50%)	1
Elevated potassium *	1/30 (3.33%)	1	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Elevated Glucose *	0/30 (0.00%)	0	1/29 (3.45%)	1	0/29 (0.00%)	0	0/8 (0.00%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain *	12/30 (40.00%)	39	8/29 (27.59%)	23	11/29 (37.93%)	22	4/8 (50.00%)	7
Nervous system disorders
headache *	3/30 (10.00%)	3	5/29 (17.24%)	5	1/29 (3.45%)	1	0/8 (0.00%)	0
Syncope *	2/30 (6.67%)	2	0/29 (0.00%)	0	0/29 (0.00%)	0	1/8 (12.50%)	1
dizziness *	4/30 (13.33%)	4	1/29 (3.45%)	1	0/29 (0.00%)	0	2/8 (25.00%)	2
Taster change *	1/30 (3.33%)	1	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Psychiatric disorders
insomnia *	1/30 (3.33%)	1	2/29 (6.90%)	2	3/29 (10.34%)	3	0/8 (0.00%)	0
irritability *	0/30 (0.00%)	0	0/29 (0.00%)	0	2/29 (6.90%)	2	0/8 (0.00%)	0
anxiety *	1/30 (3.33%)	1	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Renal and urinary disorders
Hematuria *	0/30 (0.00%)	0	0/29 (0.00%)	0	0/29 (0.00%)	0	2/8 (25.00%)	2
Urinary tract infection *	0/30 (0.00%)	0	0/29 (0.00%)	0	1/29 (3.45%)	2	2/8 (25.00%)	3
Reproductive system and breast disorders
Breast Tenderness *	5/30 (16.67%)	5	5/29 (17.24%)	6	6/29 (20.69%)	6	0/8 (0.00%)	0
gynecomastia *	4/30 (13.33%)	4	0/29 (0.00%)	0	1/29 (3.45%)	1	1/8 (12.50%)	1
urine obstruction *	0/30 (0.00%)	0	2/29 (6.90%)	2	1/29 (3.45%)	1	0/8 (0.00%)	0
Erectile dysfunction *	0/30 (0.00%)	0	1/29 (3.45%)	1	0/29 (0.00%)	0	0/8 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
dyspnea *	0/30 (0.00%)	0	0/29 (0.00%)	0	2/29 (6.90%)	2	0/8 (0.00%)	0
cough *	5/30 (16.67%)	6	4/29 (13.79%)	6	0/29 (0.00%)	0	0/8 (0.00%)	0
Shortness of breath *	1/30 (3.33%)	1	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
Skin and subcutaneous tissue disorders
rash *	5/30 (16.67%)	6	2/29 (6.90%)	2	0/29 (0.00%)	0	0/8 (0.00%)	0
pruritis *	4/30 (13.33%)	4	0/29 (0.00%)	0	0/29 (0.00%)	0	0/8 (0.00%)	0
pain at injection site *	0/30 (0.00%)	0	2/29 (6.90%)		1/29 (3.45%)	1	0/8 (0.00%)	0
increased hair growth *	0/30 (0.00%)	0	0/29 (0.00%)	0	3/29 (10.34%)	3	0/8 (0.00%)	0
Vascular disorders
Hypertension *	7/30 (23.33%)	24	4/29 (13.79%)	8	6/29 (20.69%)	6	0/8 (0.00%)	0
hot flashes *	5/30 (16.67%)	6	4/29 (13.79%)	4	2/29 (6.90%)	4	1/8 (12.50%)	1
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Samuel Denmeade, M.D.
• Organization: Johns Hopkins University School of Medicine
• Phone: 410-502-8341
• EMail: denmesa@jhmi.edu

Publications of Results:

Markowski MC, Wang H, Sullivan R, Rifkind I, Sinibaldi V, Schweizer MT, Teply BA, Ngomba N, Fu W, Carducci MA, Paller CJ, Marshall CH, Eisenberger MA, Luo J, Antonarakis ES, Denmeade SR. A Multicohort Open-label Phase II Trial of Bipolar Androgen Therapy in Men with Metastatic Castration-resistant Prostate Cancer (RESTORE): A Comparison of Post-abiraterone Versus Post-enzalutamide Cohorts. Eur Urol. 2021 May;79(5):692-699. doi: 10.1016/j.eururo.2020.06.042. Epub 2020 Jul 2.

Sena LA, Wang H, Lim ScM SJ, Rifkind I, Ngomba N, Isaacs JT, Luo J, Pratz C, Sinibaldi V, Carducci MA, Paller CJ, Eisenberger MA, Markowski MC, Antonarakis ES, Denmeade SR. Bipolar androgen therapy sensitizes castration-resistant prostate cancer to subsequent androgen receptor ablative therapy. Eur J Cancer. 2021 Feb;144:302-309. doi: 10.1016/j.ejca.2020.11.043. Epub 2020 Dec 29.

Teply BA, Wang H, Luber B, Sullivan R, Rifkind I, Bruns A, Spitz A, DeCarli M, Sinibaldi V, Pratz CF, Lu C, Silberstein JL, Luo J, Schweizer MT, Drake CG, Carducci MA, Paller CJ, Antonarakis ES, Eisenberger MA, Denmeade SR. Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. Lancet Oncol. 2018 Jan;19(1):76-86. doi: 10.1016/S1470-2045(17)30906-3. Epub 2017 Dec 14.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT02090114
• Other Study ID Numbers: J1416; NA_00093344 ( Other Identifier: JHM IRB ); 1R01CA184012-01 ( U.S. NIH Grant/Contract )
• First Submitted: March 4, 2014
• First Posted: March 18, 2014
• Results First Submitted: April 26, 2022
• Results First Posted: June 27, 2022
• Last Update Posted: June 27, 2022