Surgery With or Without Docetaxel and Leuprolide or Goserelin in Treating Patients With High-Risk Localized Prostate Cancer

This randomized trial tests whether the addition of chemohormonal therapy improves
PSA-progression free survival in patients with high risk, clinically-localized prostate
cancer. The neoadjuvant approach is taken since there appears to be a higher acceptance rate
in the prostate population for this type of therapy and several phase II trials have
demonstrated its safety. Multiple chemotherapeutic therapies have shown efficacy in advanced
prostate cancer and docetaxel has become the community standard. Many high risk patients are
initiated on LHRH agonists at or near the time of diagnosis of their prostate cancer. In
order to allow the inclusion of these patients in the protocol, enhanced enrollment and
maintain compliance with therapy, up to 3 months of androgen deprivation therapy prior to
enrollment will be permitted. This study will therefore be able to test the hypothesis that
targeting both androgen-sensitive and chemotherapy- sensitive prostate cancer cells will
improve outcomes in these high-risk patients.

OUTLINE: This is a multicenter, randomized study. Patients are stratified according to
nomogram-predicted biochemical progression-free survival at 5 years (0-20.9% vs 21-39.9% vs
40-59.9% vs ≥ 60%) and androgen-deprivation therapy prior to randomization ≤ 4 months (no vs
yes). Patients are randomized to 1 of 2 treatment arms. Please see the Arms sections for more
details.

The primary and secondary objectives are described below.

Primary:

- To determine whether treatment with neoadjuvant docetaxel and androgen deprivation therapy
prior to radical prostatectomy will increase the rate of 3-year biochemical progression-free
survival (bPFS) compared to treatment with immediate radical prostatectomy alone for
high-risk prostate cancer patients.

Secondary:

- To compare the 5-year bPFS rate, bPFS, disease progression, disease-free survival, and
overall survival of patients randomized to the two arms of this trial

- To determine the safety and tolerability of neoadjuvant docetaxel and androgen
deprivation therapy prior to surgery for high-risk patients undergoing radical
prostatectomy

- To compare the impact of neoadjuvant docetaxel and androgen deprivation therapy on time
to clinically apparent local disease recurrence and metastatic disease in high-risk
patients undergoing radical prostatectomy for clinically localized prostate cancer

- To compare the impact of neoadjuvant docetaxel and androgen deprivation therapy relative
to RP on pathologic tumor stage, frequency of lymph node metastases and positive margin
rates for high-risk patients undergoing radical prostatectomy for clinically localized
prostate cancer

- To determine if changes in serum testosterone levels will predict bPFS

- To determine prospectively whether PSA doubling time (PSADT) is a surrogate endpoint for
time to clinical metastases and overall survival

Patients are followed up to 15 years post-randomization.

1. Histologic documentation - Histologic documentation of prostatic adenocarcinoma.

Patients with small cell, neuroendocrine, or transitional cell carcinomas are not
eligible.

All eligible patients must have a known Gleason sum based on biopsy or TURP at the
time of registration.

2. Clinically localized disease - Patients must have clinical stage T1-T3a and no
radiographic evidence of metastatic disease as demonstrated by:

- EITHER CT or MRI of the abdomen and pelvis, OR endorectal MRI of the pelvis that
demonstrate no nodes > 1.5 cm. If one or more pelvic lymph node(s) measures > 1.5
cm, a negative biopsy is required. If more than one lymph node is > 1.5 cm, the
largest or most accessible node should be biopsied.

AND

- Negative bone scan (with plain films and/or MRI and/or CT scan confirmation, if
necessary). Positive PET and Prostascint scans are not considered proof of
metastatic disease.

3. Determination of high-risk status: Patients must have either:

- A Kattan nomogram predicted probability of being free from biochemical
progression at 5 years after surgery of < 60%.

OR

- Prostate biopsy Gleason sum ≥ 8 (NOTE: The Kattan nomogram probability must be
calculated for all patients, including those eligible based on Gleason sum ≥ 8
only.)

4. Prior treatment - No prior treatment for prostate cancer including prior surgery
(excluding TURP), pelvic lymph node dissection, radiation therapy, or chemotherapy.

Patients may have received up to 4 months of androgen deprivation therapy (LHRH
agonists, antiandrogens, or both) prior to being enrolled on the study.

5. Appropriate surgical candidates - Patients must be appropriate candidates for radical
prostatectomy with an estimated life expectancy > 10 years as determined by a
urologist. Evidence of underlying cardiac disease should be evaluated prior to
enrollment to ensure that patients are not at high risk of cardiac complications.

6. Clotting history - Patients with a history of deep venous thrombosis, pulmonary
embolism, and/or cerebrovascular accident or currently requiring systemic
anticoagulation are eligible provided they are determined to be candidates for radical
prostatectomy.

7. ECOG performance status: 0-2

8. Age: ≥ 18 years of age

9. Required Initial Laboratory Values:

- ANC ≥ 1500/μL

- Platelet count ≥ 150,000/μL

- Creatinine ≤ 2.0 mg/dL

- Pre-registration serum PSA level ≤ 100 ng/mL

- Bilirubin ≤ 1.5XULN (2.5XULN in patients with Gilbert's disease)

- AST/ALT ≤1.5XULN