Androgen Ablation Therapy With or Without Chemotherapy in Treating Patients With Metastatic Prostate Cancer

OBJECTIVES:

Primary

- Evaluate the ability of early chemotherapy to improve overall survival of patients
commencing androgen deprivation for metastatic prostate cancer.

Secondary

- Determine whether early chemotherapy can increase the time to clinical progression
(radiographic or symptomatic deterioration due to disease) over hormonal therapy alone.

- Determine whether early chemotherapy can increase the time to development of
hormone-refractory disease over hormonal therapy alone.

- Determine whether early chemotherapy can increase the time to serological progression
over hormonal therapy alone.

- Determine rates of biochemical response at 6 months and 12 months in the chemohormonal
arm versus the hormonal therapy alone arm.

- Determine the frequency of adverse events and the tolerability of chemotherapy combined
with hormonal therapy versus hormonal therapy alone.

- Determine whether the postulated clinically meaningful increase in disease control is
associated with an alteration in overall quality of life using the Functional Assessment
of Cancer Therapy-Prostate questionnaire.

- Determine the ability of prostate-specific antigen (PSA) changes to be a surrogate for
clinical benefit from therapy and overall survival.

Tertiary

- Determine whether there are proteins differentially translated from the genome in
hormone-sensitive prostate cancer, prostate cancer that has responded to hormonal
therapy, and hormone-refractory prostate cancer.

- Determine the frequency of constitutive polymorphisms of enzymes involved in steroid
metabolism and other carcinogenic processes.

- Determine whether the amount and frequency of certain carcinogenic proteins in prostate
cancer tissue such as C-X-C chemokine receptor type 4 (CXCR-4) and manganese superoxide
dismutase can be correlated with a poor prognosis.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (≥
70 vs < 70), ECOG performance status (0-1 vs 2), combined androgen blockade for > 30 days
(yes vs no), duration of prior adjuvant hormonal therapy (> 12 months vs ≤ 12 months),
concurrent bisphosphonate use (yes vs no), and volume of disease (low vs high). Patients are
randomized to 1 of 2 treatment arms.

- Arm A (Androgen-Deprivation Therapy and Docetaxel): Patients receive
androgen-deprivation therapy (including luteinizing hormone-releasing hormone [LHRH]
agonist therapy, LHRH antagonist therapy, or surgical castration). Patients also receive
docetaxel intravenously (IV) over 1 hour on day 1. Treatment with docetaxel repeats
every 21 days for up to 6 courses in the absence of disease progression or unacceptable
toxicity.

- Arm B (Androgen-Deprivation Therapy alone): Patients receive androgen-deprivation
therapy (as in arm A) alone.

Quality of life is assessed at baseline and at months 3, 6, 9 and 12.

After completion of study treatment, patients are followed up periodically for up to 10
years.

Inclusion Criteria:

- Histologically or cytologically confirmed prostate cancer

- Metastatic disease

- On androgen-deprivation therapy for < 120 days

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

- PS 2 eligible only if decline in PS is due to metastatic prostate cancer

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- Bilirubin ≤ upper limit of normal (ULN)

- Alanine aminotransferase (ALT) ≤ 2.5 times ULN

- Creatinine clearance ≥ 30 mL/min

- Prothrombin time (PT) and international normalized ratio (INR) ≤ 1.5 times ULN (unless
on therapeutic anticoagulation)

- Partial thromboplastin time (PTT) ≤ 1.5 times ULN (unless on therapeutic
anticoagulation)

- Fertile patients must use effective contraception

- At least 4 weeks since prior major surgery and recovered from all toxicity prior to
randomization

- Prior adjuvant or neoadjuvant hormonal therapy allowed provided the following are
true:

- Therapy was discontinued ≥ 12 months ago AND there is no evidence of disease, as
defined by 1 of the following:

- PSA < 0.1 ng/dL after prostatectomy plus hormonal therapy

- PSA < 0.5 ng/dL and has not doubled above nadir after radiotherapy plus
hormonal therapy

- Therapy lasted no more than 24 months

- Last depot injection must have expired by the 24-month mark

- Prior palliative radiotherapy allowed if commenced within 30 days before starting
androgen deprivation

- Anti-androgen therapy allowed as single-agent therapy ≤ 7 days before medial
castration to prevent flare

- More than 30 days (or 6 half-lives) (whichever is longer) since prior participation in
another clinical trial

- Concurrent participation in nontherapeutic trials allowed

- Concurrent antiandrogen therapy (e.g., bicalutamide or flutamide) allowed, but not as
sole hormonal therapy

Exclusion Criteria:

- Prostate-specific antigen (PSA) level has risen and met criteria for progression from
its lowest point between the start of androgen-deprivation therapy and randomization

- Prior malignancy in the past 5 years except for basal cell or squamous cell carcinoma
of the skin

- Other malignancies that are considered to have low potential to progress (e.g.,
grade 2, T1a transitional cell carcinoma) may be allowed if approved by study
chair

- Peripheral neuropathy > grade 1

- History of severe hypersensitivity reaction to docetaxel or other drugs formulated
with polysorbate 80

- Active cardiac disease, including the following:

- Active angina

- Symptomatic congestive heart failure

- Myocardial infarction within the past 6 months

- Prior chemotherapy in adjuvant or neoadjuvant setting

- Prior hormone therapy in the metastatic setting

- Concurrent 5-alpha reductase inhibitors

- Simultaneous enrollment on Cancer and Leukemia Group B (CALGB) 90202