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

A Randomized, Double-blind, Placebo-controlled Phase III Trial to Evaluate the Effectiveness of a Phosphodiesterase 5 Inhibitor, Tadalafil, in Prevention of Erectile Dysfunction in Patients Treated With Radiotherapy for Prostate Cancer

RATIONALE: Tadalafil may help prevent erectile dysfunction (ED) 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 Common Toxicity Criteria for Adverse Effects (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 phosphodiesterase type 5 (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 vesicles 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.

Inclusion Criteria:

1. Clinical stage T1b-T2b (AJCC, 6th ed.) adenocarcinoma of the prostate within 6 months of registration

2. Clinically negative lymph nodes as established by imaging (pelvic ± abdominal CT or MR), nodal sampling, or dissection within 3 months prior to registration. Patients with lymph nodes equivocal or questionable by imaging are eligible if the nodes are ≤ 1.5 cm. Lymph node assessment is optional, and at investigator discretion, for patients with Gleason Score <7.

3. No evidence of bone metastases (M0) on bone scan within 3 months prior to registration. Equivocal bone scan findings are allowed if plain films are negative for metastasis. Bone metastases assessment is optional, and at investigator discretion, for patients with Gleason Score <7.

4. Baseline serum prostatic specific antigen (PSA) value performed with an FDA-approved assay (e.g., Abbott, Hybritech) within 3 months prior to registration.

   -4.1 Any of the following combinations of factors (NOTE: tumor found in 1 or both lobes on biopsy, but not palpable, will not alter T stage):

   • T1b-T2b disease, Gleason Score <7 and serum total PSA that is <20 ng/ml or
   • T1b-T2b disease, Gleason Score ≥7 and PSA that is <15 ng/ml

5. Serum total testosterone level prior to the initiation of radiation therapy (RT) within normal range according to institutional guidelines

6. Zubrod Performance Status 0 or 1 (Appendix III)

7. Age ≥ 18 years

8. Treatment that will consist of either external beam RT alone to the prostate ± seminal vesicles only at a dose between 75 Gy and 79.2 Gy or brachytherapy alone (NOTE: treatment with combined external RT and brachytherapy excludes patient participation)

9. Pretreatment (before starting prostate cancer treatment) erectile function as measured by IIEF Question 1, "How often were you able to get an erection during sexual activity?" - with responses of:

   • "sometimes (about half the time)" [response 3] or
   • "most times (much more than half the time)" [response 4] or
   • "almost always/always" [response 5]

10. History of prior tadalafil use: Document usual dosage per sexual encounter, date of last dose, and patient's response (No; Yes-Unsatisfactory Response; Yes-Satisfactory Response). Regardless of past experience, the patient is eligible if he agrees to adhere to protocol and take only tadalafil or placebo prescribed on study.

11. Although patients with partners are targeted for recruitment, patients without partners or without partners willing to participate are eligible. Patients (and spouses/partners, if willing to participate) must be able to provide study-specific informed consent.

Exclusion Criteria:

1. The patient's participation in another medical research study that involves the treatment of ED

2. Previous or concomitant invasive cancer (American Joint Committee on Cancer [AJCC] Stage >0), other than localized basal cell or squamous cell skin carcinoma (AJCC Stage 0-II), or a hematological malignancy (e.g., leukemia, lymphoma, myeloma) unless continually disease free for at least 5 years

3. History of myocardial infarction within the last year

4. Heart failure in the last 6 months

5. Uncontrolled arrhythmias, hypotension (<90/50mm Hg), or uncontrolled hypertension (>170/100 mm Hg)

6. Stroke within the last 6 months

7. Use of luteinizing hormone-releasing hormone (LHRH) agonist androgen suppression (e.g., Lupron, Zoladex), anti-androgen (e.g., Casodex, Eulexin, Nilandron), or estrogenic (e.g., diethylstilbestrol) agents within the last 6 months

8. Current use of any organic nitrate or as needed nitrates (e.g., use of nitroglycerin)

9. Current use of cimetidine, ketoconazole, itraconazole, erythromycin, or ritonavir

10. Known moderate to severe renal insufficiency or end-stage renal disease

11. Known severe hepatic impairment

12. Use of mechanical (vacuum) devices, intracorporeal, intraurethral, topical, or oral (sildenafil, tadalafil, vardenafil) agents as therapy for ED or supplements to enhance sexual function within 5-7 days prior to the start of RT. Patients who discontinue these therapies remain eligible if they can meet eligibility criteria

13. Pretreatment (before starting prostate cancer treatment) ED as measured by IIEF Question 1, "How often were you able to get an erection during sexual activity?" - with responses of:

    • "no sexual activity" [response 0] or
    • "almost never/never" [response 1] or
    • "a few times (much less than half the time)" [response 2]

14. Prior penile implant or history of bilateral orchiectomy

15. Prior prostatectomy, prostatic cryosurgery or high-intensity focused ultrasound (HIFU), radionuclide prostate brachytherapy, or chemotherapy for prostate cancer

16. Prior or anticipated combined external RT and brachytherapy

17. Prior or anticipated external RT to the pelvic ± para-aortic lymph nodes

18. Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. Protocol-specific requirements may also exclude immunocompromised patients.

19. Anatomical genital abnormalities or concurrent conditions that in the estimation of the physician would prohibit sexual intercourse or prevent study completion

20. Major medical or psychiatric illness which, in the opinion of the investigator, would prevent completion of treatment or would interfere with follow-up