The androgen biosynthesis inhibitor abiraterone acetate (Zytiga) has been shown to increase radiographic progression-free survival and delay clinical decline and initiation of chemotherapy in a clinical trial in castration-resistant patients with metastatic prostate cancer who have had no prior chemotherapy. A trend toward improved overall survival was also observed with abiraterone treatment.
The trial, recently reported by Charles J. Ryan, MD, of the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, and colleagues in The New England Journal of Medicine, provided the basis for the recent expanded indication for abiraterone in patients with metastatic disease and no prior chemotherapy.1 The prior indication for abiraterone was limited to patients who had previously received chemotherapy including docetaxel.2
In this trial, 1,088 patients were randomly assigned to receive abiraterone at 1,000 mg daily plus prednisone at 5 mg twice daily (n = 546) or placebo plus prednisone (n = 542). Patients had to have no or mild pain symptoms, prostate-specific antigen (PSA) or radiographic progression in soft tissue or bone, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and ongoing androgen deprivation with a serum testosterone level of less than 50 ng/dL. Patients with visceral metastases who had received previous therapy with ketoconazole lasting more than 7 days were excluded.
Baseline characteristics were balanced between the two groups. Overall, patients had a median age of 70 years, 95% were Caucasian, and ECOG performance status was 0 in 76% of patients and 1 in 24%. Treatment continued until radiographic or clinical disease progression, unacceptable toxicity, or withdrawal. The coprimary endpoints were radiographic progression-free survival and overall survival.
Benefits in Survival across Subgroups
The study was unblinded after the second planned interim analysis, which occurred when 43% of the expected deaths had occurred. The median follow-up for all patients was 22.2 months.
On the first interim analysis (which occurred when 13% of expected deaths had occurred), abiraterone was associated with a significant 57% reduction in risk for radiographic progression (median radiographic progression-free survival not reached vs 8.3 months, hazard ratio [HR] = 0.43, P < .001). At the second interim analysis, median radiographic progression-free survival was 16.6 months in the abiraterone group vs 8.3 months in the placebo group, representing a 47% reduction in risk of progression (HR = 0.53, P < .001).
At the second interim analysis, death had occurred in 27% of the abiraterone group vs 34% of the placebo group. Median overall survival was not reached vs 27.2 months; the 25% reduction in risk for death in the abiraterone group (HR = 0.75, P = .01) indicated a strong trend toward mortality reduction but did not reach the prespecified boundary for significance (P ≤ .001). Final overall survival results are awaited.
The benefit of abiraterone in prolonging radiographic progression-free survival was significant across all subgroups (ECOG performance status 0 or 1, brief pain inventory-short form score 0–1 or 2–3, presence/absence of bone metastases at entry, age, region, and high or low PSA, lactate dehydrogenase, and alkaline phosphatase). Hazard ratios for overall survival favored abiraterone for all subgroups and were significant for some.
Prolonged Time to Opiate Use and Chemotherapy
Abiraterone treatment was also associated with prolonged median times to decline in ECOG performance status (12.3 vs 10.9 months, HR = 0.82, P = .005), initiation of cytotoxic chemotherapy (25.2 vs 16.8 months, HR = 0.58, P < .001), opiate use for cancer-related pain (not reached vs 23.7 months, HR = 0.69, P < .001), PSA progression (11.1 vs 5.6 months, HR = 0.49, P < .001), and worsening in health-related quality of life as indicated by decline in the Functional Assessment of Cancer–Prostate total score (12.7 vs 8.3 months, HR = 0.78, P = .003).
No New Safety Signals
The most common adverse events in the abiraterone group were fatigue (39% vs 34% in the prednisone-alone group), back pain (32% vs 32%), and arthralgia (28% vs 24%). Grade 3 or 4 adverse events occurred in 48% of abiraterone patients vs 42% of placebo patients, serious adverse events occurred in 33% vs 26%, and adverse events resulted in treatment discontinuation in 10% vs 9% and in dose modification or interruption in 19% vs 12%. Adverse events led to death in 4% vs 2%, with the most common cause being events related to disease progression (0.6% of each group).
Cardiac and Mineralocorticoid-related Toxicities
With regard to adverse events of special interest based on earlier abiraterone studies, grade 3 or 4 hypertension (4% vs 3%), cardiac disorders (6% vs 3%, including atrial fibrillation in 1% vs < 1%), increased ALT (5% vs < 1%), and increased AST (3% vs < 1%) were more common with abiraterone. Overall, adverse events classified as cardiac disorders occurred in 19% of abiraterone patients and 16% of placebo patients. Mineralocorticoid-related toxicities, including hypertension (22% vs 13%), hypokalemia (17% vs 13%), and fluid retention/edema (28% vs 24%), were more common in the abiraterone group, with most of the adverse events being grade 1 or 2.
The authors noted that safety of abiraterone in this study was similar to that observed in the study of patients who received abiraterone after docetaxel chemotherapy,2 with no toxic effects unique to the previously untreated population being detected. They concluded, “The results show benefit from the use of abiraterone in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer who have not received previous chemotherapy. ■
For more on use of abiraterone in the clinic, see page 38.
Disclosure: Dr. Ryan has received grant support (via his institution) from Cougar Biotechnology/Janssen, consultancy fees from Cougar Biotechnology/Janssen, Millenium, and Sanofi-Aventis, and grants or grants pending from Novartis, Aragon, and Medivation.
1. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368:138-148, 2013.
2. de Bono JS, Logothetis CJ, Molina A, et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995-2005, 2011.