Tadalafil in Preventing Erectile Dysfunction in Patients With Prostate Cancer Treated With Radiation Therapy

• Spontaneous (off-drug) EF at years 1 and 2 [ Designated as safety issue: No ]
• Overall sexual function as measured by the IIEF at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Patient and partner overall sexual satisfaction as measured by SAQ at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Patient and partner marital adjustment as measured by the Locke's Marital Adjustment Test at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Patient-related predictors of EF at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Adverse events according to CTCAE v4.0 criteria [ Designated as safety issue: Yes ]
• Patient follow-up treatment for erectile dysfunction at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Radiotherapy factors associated with spontaneous (off-drug) EF at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Number of patients screened for inclusion, number presented the study, number who refuse, and number accrued [ Designated as safety issue: No ]

• Spontaneous (off-drug) EF at years 1 and 2 [ Designated as safety issue: No ]
• Overall sexual function as measured by the IIEF at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Patient and partner overall sexual satisfaction as measured by SAQ at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Patient and partner marital adjustment as measured by the Locke's Marital Adjustment Test at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Patient-related predictors of EF at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Adverse events according to CTCAE v3.0 criteria [ Designated as safety issue: Yes ]
• Patient follow-up treatment for erectile dysfunction at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Radiotherapy factors associated with spontaneous (off-drug) EF at weeks 28-30 and years 1 and 2 [ Designated as safety issue: No ]
• Number of patients screened for inclusion, number presented the study, number who refuse, and number accrued [ Designated as safety issue: No ]

RATIONALE: Tadalafil may help prevent erectile dysfunction in patients with prostate cancer that has been treated with radiation therapy. It is not yet known whether tadalafil is more effective than a placebo in preventing erectile dysfunction.

PURPOSE: This randomized phase III trial is studying tadalafil to see how well it works compared with a placebo in preventing erectile dysfunction in patients with prostate cancer treated with radiation therapy.

OBJECTIVES:

Primary

• To determine whether tadalafil maintains spontaneous (off-drug) erectile function, as measured by the International Index of Erectile Function (IIEF) as compared to placebo at weeks 28-30 after initiation of radiotherapy in patients with prostate cancer.

Secondary

• Determine the difference in spontaneous (off-drug) erectile function between tadalafil and placebo at 1 and 2 years.
• Determine the difference in overall sexual function as measured by the IIEF between tadalafil and placebo at weeks 28-30 and at 1 and 2 years.
• Determine differences in patient and partner overall sexual satisfaction as measured by the Sexual Adjustment Questionnaire (SAQ) between tadalafil and placebo at weeks 28-30 and at 1 and 2 years.
• Determine differences in patient and partner marital adjustment as measured by Locke's Marital Adjustment Test (LMAT) between tadalafil and placebo at weeks 28-30 and at 1 and 2 years.
• Determine associations between patient and partner overall sexual satisfaction as measured by SAQ and patient and partner marital adjustment as measured by LMAT at weeks 28-30 and at 1 and 2 years.
• Determine patient-related factors (i.e., age, pretreatment sexual response, tobacco use, and comorbidities) that may predict response to tadalafil therapy at weeks 28-30 and at 1 and 2 years.
• Determine the difference in adverse events between tadalafil and placebo as assessed by CTCAE v3.0 criteria.

Tertiary

• Characterization of preference and erectile function among patients who choose to stay on (or if on placebo, to start) tadalafil, a PDE5 inhibitor other than tadalafil, a non-PDE5-inhibitor erectile aide, or no PDE5 inhibitor or erectile aide at 28-30 weeks and at 1 and 2 years.
• Identification of radiotherapy factors (i.e., modality, prescribed total dose, planning target volume margin, penile bulb dose-volume parameters) associated with erectile function.
• Evaluation of the number of patients screened for eligibility, the number eligible that are presented the study, the number who refuse, and the number who are accrued.

OUTLINE: This is a multicenter study. Patients are stratified according to age (≤ 65 years vs > 65 years) and radiotherapy treatment (external beam radiation therapy vs brachytherapy*). Patients are randomized to 1 of 2 treatment arms.

NOTE: * Radiotherapy start date for brachytherapy patients is the date of the procedure.

All patients undergo either external beam radiotherapy alone to the prostate ± seminal vesicals only or low-dose rate permanent brachytherapy alone.

• Arm I: Beginning ≤ 7 days after the start of radiotherapy, patients receive oral tadalafil once daily for 24 weeks in the absence of disease progression or unacceptable toxicity.
• Arm II: Beginning ≤ 7 days after the start of radiotherapy, patients receive oral placebo once daily for 24 weeks in the absence of disease progression or unacceptable toxicity.

Patients complete the International Index of Erectile Function (IIEF), the Sexual Adjustment Questionnaire (SAQ), the Locke's Marital Adjustment Test (LMAT) (if applicable), and the Expanded Prostate Cancer Index Composite Sexual Medications and Devices Evaluations Supplement questionnaires periodically. Partners or spouses complete the SAQ-Partner, LMAT (if applicable), and IIEF questionnaires periodically.

After completion of study treatment, patients are followed at 28-30 weeks, and annually for up to 2 years.

• Prostate Cancer
• Sexual Dysfunction

• Drug: tadalafil
  Given orally
• Other: placebo
  Given orally

• Experimental: Arm I
  Beginning ≤ 7 days after the start of radiotherapy, patients receive oral tadalafil once daily for 24 weeks.
  Intervention: Drug: tadalafil
• Placebo Comparator: Arm II
  Beginning ≤ 7 days after the start of radiotherapy, patients receive oral placebo once daily for 24 weeks.
  Intervention: Other: placebo

DISEASE CHARACTERISTICS:

• Meets 1 of the following criteria:

  • Diagnosis of adenocarcinoma of the prostate within the past 6 months

    • Clinical stage T1b-T2b
    • No distant metastases

    • Clinically negative lymph nodes established by imaging (pelvic ± abdominal CT or MRI), nodal sampling, or dissection within the past 3 months

      • Patients with lymph nodes equivocal or questionable by imaging are eligible provided the nodes are ≤ 1.5 cm
      • Lymph node assessment is optional and at the investigator's discretion for patients with Gleason score < 7

    • No evidence of bone metastases on bone scan within the past 3 months

      • Equivocal bone scan findings allowed provided plain films are negative for metastasis
      • Bone metastasis assessment is optional and at the investigator's discretion for patients with Gleason score < 7

    • Baseline serum PSA value performed with an FDA-approved assay within the past 3 months and meets 1 of the following criteria:

      • Gleason score < 7 and PSA < 20 ng/mL
      • Gleason score ≥ 7 and PSA < 15 ng/mL
    • Planning to undergo treatment with either external radiotherapy alone to the prostate ± seminal vesicals only at a dose of 75-79.2 Gy OR brachytherapy alone
    • Pretreatment erectile function as measured by International Index of Erectile Function questionnaire response 3, 4, or 5 on question 1

  • Spouse or partner of these patients (optional)

    • Male or female

PATIENT CHARACTERISTICS:

• Zubrod performance status 0-1
• Serum total testosterone level normal prior to the initiation of radiotherapy
• No myocardial infarction within the past year
• No heart failure within the past 6 months
• No stroke within the past 6 months
• No uncontrolled arrhythmias, hypotension (BP < 90/50 mm Hg), or uncontrolled hypertension (BP > 170/100 mm Hg)
• No known moderate to severe renal insufficiency or end-stage renal disease
• No known severe hepatic impairment
• No prior or concurrent invasive cancer (stage > 0) except for localized basal cell or squamous cell skin carcinoma (stage 0-II), or a hematological malignancy (e.g., leukemia, lymphoma, myeloma) unless disease-free ≥ 5 years
• No known AIDS based upon current CDC definition
• No anatomical genital abnormalities or concurrent conditions that, in the estimation of the physician, would prohibit sexual intercourse or prevent study completion
• No major medical or psychiatric illness that, in the opinion of the investigator, would prevent completion of treatment or would interfere with follow up

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Prior tadalafil allowed
• No prior penile implant or history of bilateral orchiectomy
• No prior prostatectomy, prostatic cryosurgery, high-intensity focused ultrasound, radionuclide prostate brachytherapy, or chemotherapy for prostate cancer
• No prior or anticipated combined external radiotherapy and brachytherapy
• No prior or anticipated external radiotherapy to the pelvic ± para-aortic lymph nodes
• More than 6 months since prior leuteinizing hormone-releasing hormone agonist androgen suppression (e.g., leuprolide acetate, goserelin), antiandrogen (e.g., flutamide, bicalutamide, or nilutamide), or estrogenic (e.g., diethylstilbestrol) agents
• At least 5-7 days since prior use of mechanical (vacuum) devices, intracorporeal, intraurethral, topical, or oral (sildenafil, tadalafil, vardenafil) agents as therapy for erectile dysfunction (ED) or supplements to enhance sexual function
• No other concurrent medical research study that involves the treatment of ED
• No concurrent use of any organic nitrate or as-needed nitrates (e.g., use of nitroglycerin)
• No concurrent cimetidine, ketoconazole, itraconazole, erythromycin, or ritonavir