Men with metastatic castration-resistant prostate cancer (CRPC) had a four-month improvement in survival when treated with the androgen biosynthesis inhibitor abiraterone (Zytiga) after progression on docetaxel, results of an international trial showed.
Men treated with abiraterone had a median overall survival of about 15 months, compared with 11 months for a placebo-treated control group.
Analysis of time to biochemical progression, progression-free survival, and PSA response rate showed statistically significant advantages for abiraterone, investigators reported in the May 26 issue of the New England Journal of Medicine.
"Increased survival was observed in all patient subgroups, and the superiority of the treatment group was shown across all prespecified secondary endpoints," Johann S. de Bono, MD, of the Royal Marsden Hospital in Surrey, England, and co-authors wrote in summary.
"The use of hormonal agents is typically not considered in patients who have received chemotherapy. These results show that continued androgen-receptor signaling contributes to disease progression, and they provide support for the evaluation of other endocrine therapies in this stage of the disease."
The results provided the basis for FDA approval of abiraterone last month.
Androgen deprivation has represented the standard of care for advanced prostate cancer for the past 70 years. The treatment leads to PSA response, tumor regression, and symptom relief in most patients.
However, responses are short lived, the authors noted, as rising PSA levels herald reactivation of androgen-receptor signaling and the transition to an inevitably fatal castration-resistant state. To date, no form of endocrine therapy has demonstrated the ability to improve survival in CRPC.
Three nonhormonal therapies have been found to prolong survival: docetaxel as first-line cytotoxic therapy, cabazitaxel as second-line cytotoxic therapy, and the immunotherapeutic agent sipuleucel-T.
A molecular alteration unique to CRPC results in upregulation of androgen biosynthesis enzymes, leading to increased intratumoral androgen concentrations. Androgen levels inside the tumor may exceed those in circulation, the authors noted.
Abiraterone acetate blocks the cytochrome P450 c17 (CYP17) enzyme that has a critical role in testosterone synthesis, which, in turn, leads to inhibition of androgen biosynthesis by the adrenals and testes and within the tumor.
Phase I-II trials showed that abiraterone had antitumor activity in patients with progressive CRPC previously treated with chemotherapy or that were chemotherapy naive. The promising results led to a large phase III, randomized trial involving investigators at 147 sites in 13 countries.
The trial involved patients with CRPC previously treated with docetaxel. Investigators randomized 1,195 men 2:1 to abiraterone plus prednisone or placebo plus prednisone. The primary endpoint was overall survival, and secondary endpoints included time to PSA progression, PFS, and PSA response rate.
The trial ended prematurely when a planned interim analysis revealed a significant survival advantage for the abiraterone arm.
After a median follow-up of 13 months, patients treated with abiraterone and prednisone had a median overall survival of 14.8 months compared with 10.9 months in the placebo-prednisone group, a 35% reduction in the hazard ratio (P<0.001). Analysis of key secondary outcomes showed significant advantages for abiraterone therapy:
* Time to PSA progression, 10.2 versus 6.6 months, P<0.001
* PFS, 5.6 versus 3.6 months, P<0.001
* PSA response rate, 29% versus 6%, P<0.001
The most common adverse events were steroid related and included fluid retention, hypertension, and hypokalemia, which occurred more often in the abiraterone arm.
Results of the trial "provide a proof of principle that metastatic castration-resistant prostate cancer remains androgen-driven," authors of an accompanying editorial wrote.
"Although this study led to the approval of abiraterone by the Food and Drug Administration ... for patients who had received docetaxel, these results provide sufficient evidence of efficacy to justify the use of abiraterone in all patients with metastatic castration-resistant prostate cancer -- for example, even those with no previous chemotherapy treatment," added Emmanuel S. Antonarakis, MD, and Mario A. Eisenberg, MD, of Johns Hopkins.
However, the editorialists questioned whether overall survival might represent too lofty a goal for new agents developed to treat CRPC.
"Survival is likely to become harder to assess unless we are able to control for the influence of subsequent treatments on survival," they continued.
"More recent trials in metastatic castration-resistant prostate cancer have used coprimary endpoints, such as progression-free survival and overall survival, in an attempt to validate progression-free survival as a clinically meaningful and more feasible endpoint."
If regulatory agencies continue to consider chemotherapy-treated patients as a distinct group, that could further complicate future trials. Additionally, placebo-controlled trials in metastatic CRPC might not be ethical or feasible in the future, given the availability of therapies known to improve survival.
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