Tadalafil 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