Dawning of the Age of Chemotherapy for Prostate Cancer

Traditionally, prostate cancer has been believed to be a “chemoresistant” disease. Indeed, until recently the only US Food and Drug Administration-approved chemotherapeutic regimen for prostate cancer, mitoxantrone and prednisone, won approval on the basis of quality-of-life improvements despite showing no effect on overall survival.¹ However, this paradigm of prostate cancer as a “chemoresistant” disease has been forever changed by 2 recently published phase III studies.

Docetaxel Plus Prednisone or Mitoxantrone Plus Prednisone for Advanced Prostate Cancer

Tannokc IF, de Wit R, Berry WR, et al.

N Engl J Med.2004;351:1502–1512.

This study, known as TAX 327, was a multinational, phase III, randomized, nonblinded clinical trial of docetaxel (Taxotere®; Aventis Pharmaceuticals, Parsippany, NJ) plus prednisone versus mitoxantrone plus prednisone for hormone-refractory prostate cancer. There were 3 treatment arms: docetaxel plus prednisone once weekly, docetaxel plus prednisone once every 3 weeks, and mitoxantrone plus prednisone. Entry criteria included metastatic prostate cancer that had progressed while patients were receiving antihormonal therapy. In addition, patients could not have received prior chemotherapy except estramustine and must not have taken antiandrogens for at least 4 weeks to avoid confounding response from antiandrogen withdrawal. Docetaxel was given as an intravenous (IV) infusion of 75 mg/m² (once-every-3-weeks dosing) or 30 mg/m² (once-weekly dosing). Mitoxantrone was given as an IV infusion of 12 mg/m² every 3 weeks. All treatment arms also received prednisone 5 mg orally twice daily. The primary end point was death. Secondary end points included quality of life, as measured by the Functional Assessment of Cancer Therapy-Prostate questionnaire, measurements of pain as determined by the Present Pain Intensity Index, and adverse events.

A total of 1006 patients were randomized to 1 of the 3 treatment arms. Twelve percent of patients in each arm were found to be ineligible. The treatment arms were well balanced. Median age was 68 years. A total of 45% of patients had pain at baseline, and 40% had soft tissue metastasis. The most common indicator of disease progression before randomization was a rising prostate-specific antigen (PSA) level. Median PSA levels among the treatment arms ranged from 108 ng/mL to 123 ng/mL. A total of 99% of the patients received at least 1 cycle of the prescribed chemotherapy. However, patients randomized to docetaxel every 3 weeks tended to receive more cycles (median 9.5) than men randomized to either the weekly docetaxel (median 4 cycles) or the mitoxantrone (median 5 cycles) arms. After progression patients could receive any therapy, and approximately 1 in 4 patients received the drug to which they were not originally assigned after progression (ie, those assigned to mitoxantrone received docetaxel upon progression, and vice versa).

During a median follow-up of nearly 21 months, there were 557 deaths. Docetaxel every 3 weeks was associated with a significantly lower relative risk (RR) of death relative to mitoxantrone (RR, 0.76; 95% confidence interval [CI], 0.62–0.94; P = .009). There was also a trend for improved survival in the docetaxel weekly arm relative to mitoxantrone, though this did not reach statistical significance (RR, 0.91; 95% CI, 0.75–1.11; P = .36). Median survival in the once-every-3-weeks docetaxel arm was 18.9 months, compared with 17.4 months in the weekly docetaxel arm and 16.5 months in the mitoxantrone arm. In addition, both docetaxel arms were associated with improvements in pain response, PSA response, and quality of life. In terms of adverse events, there was a trend for increased toxicity with the docetaxel regimens (26%–29% of patients having a least one adverse event vs 20% with mitoxantrone). Interestingly, the toxicity profiles of the once-weekly and once-every-3-weeks docetaxel regimens were very similar: there was no reduction in toxicity with lower doses of docetaxel given more often. Treatment-related deaths were rare (≤ 1%) in all treatment arms.

Docetaxel and Estramustine Compared with Mitoxantrone and Prednisone for Advanced Refractory Prostate Cancer

Petrylack, DP, Tangen CM, Hussain MHA, et al.

N Engl J Med. 2004;351:1513–1520

This study, supported by the Southwest Oncology Group (SWOG) and known as SWOG Intergroup protocol 99-16, was a phase III, randomized, nonblinded clinical trial of docetaxel plus estramustine versus mitoxantrone plus prednisone for hormone-refractory prostate cancer. Entry criteria were similar to those of the TAX 327 study and included metastatic prostate cancer that had progressed while the patient was receiving antihormonal therapy. Patients were allowed to have received 1 prior chemotherapy regimen, except estramustine, taxanes, anthracyclines, or mitoxantrone. Patients must not have been taking antiandrogens for at least 4 weeks to avoid confounding response from antiandrogen withdrawal. Docetaxel was given as an IV infusion of 60 mg/m² every 3 weeks, and the dose was escalated to 75 mg/m² if no grade 3 or 4 toxicity occurred after the first cycle. Patients randomized to the docetaxel arm also received estramustine 280 mg orally, 3 times per day, on days 1 through 5 of each 21-day cycle. Mitoxantrone was given as an IV infusion of 12 mg/m² every 3 weeks, which was increased to 14 mg/m² every 3 weeks if no grade 3 or 4 toxicity occurred after the first cycle. With mitoxantrone, patients also received prednisone 5 mg orally twice per day. The primary end point was overall survival. Secondary end points included progression-free survival, the objective response rate, the rate of PSA response (defined as a decline in the serum PSA level of at least 50%), and adverse events. Because after enrollment there were reports that estramustine could be related to increased cardiovascular events, the protocol was amended to include warfarin 2 mg and aspirin 325 mg daily for patients in the docetaxel/estramustine arm.

A total of 770 patients were randomized to docetaxel/estramustine or mitoxantrone/prednisone, of whom 674 were eligible for the study. The arms were well matched, with median PSA values of 84 ng/mL to 90 ng/mL. After 32 months of follow-up, 452 patients had died. Docetaxel/estramustine was associated with a significantly reduced risk of death (hazard ratio, 0.80; 95% CI, 0.67–0.97; P = .02). This translated into an approximately 2-month survival advantage for docetaxel/estramustine: 17.5 months vs. 15.6 months. Docetaxel was also associated with delayed progression-free survival (P < .001) and improvement in PSA response (P < .001), though there were no significant differences in partial response rate or pain relief. Overall, adverse events were more common among patients receiving docetaxel/estramustine. Specifically, docetaxel/estramustine was associated with significantly higher rates of grade 3 or 4 neutropenic fevers, cardiovascular events, nausea and vomiting, metabolic disturbances, and neurologic events.

To summarize these 2 ground-breaking studies, docetaxel given every 3 weeks but not weekly was associated with a significantly prolonged survival of approximately 2 months in both studies for men with hormone-refractory prostate cancer. This was associated with improved pain response (in 1 of the 2 studies), PSA response, and quality of life. Adding estramustine did not improve the survival benefit (still 2 months) and might have increased the risk of adverse events. As a result of these 2 studies, the US Food and Drug Administration has approved the use of docetaxel for late-stage hormone-refractory prostate cancer. More importantly, these studies have disproved the old myth that prostate cancer is a “chemoresistant” disease. The next step, which is ongoing, is to evaluate whether earlier use of chemotherapy will result in an even greater survival advantage. It is hoped that these studies are just the beginning, and it is likely that we are now at the dawn of the age of chemotherapy for prostate cancer.