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