Androgen Ablation Therapy With or Without Chemotherapy in Treating Patients With Metastatic Prostate Cancer
Androgen Ablation Therapy With or Without Chemotherapy in Treating Patients With Metastatic Prostate Cancer
RATIONALE: Androgens can cause the growth of prostate cancer cells. Androgen ablation therapy
 may stop the adrenal glands from making androgens. Drugs used in chemotherapy, such as
 docetaxel, work in different ways to stop the growth of tumor cells, either by killing the
 cells or by stopping them from dividing. It is not yet known whether androgen-ablation
 therapy is more effective with or without docetaxel in treating metastatic prostate cancer.

 PURPOSE: This randomized phase III trial is studying androgen-ablation therapy and
 chemotherapy to see how well they work compared to androgen-ablation therapy alone 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