In this multi-national, randomized, placebo-controlled study, abiraterone plus low-dose prednisone resulted in prolonged radiographic progression free survival (HR = 0.43) and delayed the time to initiation of opiate analgesia, treatment with cytotoxic chemotherapy, deterioration of performance status, PSA progression, onset of pain, and degradation of HRQOL. The PSA response proportion and time to disease progression in the current study are consistent with that observed in earlier phase 1/2 studies of abiraterone.20–22
Additionally, a strong trend toward improved survival (HR = 0.75) was evident at 43% of the prespecified total number of events required for the final analysis. This broad and consistent pattern of benefit resulted in the unanimous decision of the IDMC to recommend unblinding and crossover of placebo patients to abiraterone treatment.
Despite the various therapies available for men with mCRPC, a need persists for effective non-toxic agents that can improve and maintain quality and duration of life while preventing the morbidity associated with disease progression.25
Second-line hormonal manipulation with antiadrogens, diethylstilbesterol, and ketoconazole has long been utilized despite the absence of randomized clinical data to support its use.8
The pattern of use persisted despite the availability of docetaxel and sipuleucel-T, where application of the former is limited by toxicity while the latter is limited by a lack of demonstrable antitumor activity, despite a survival benefit. The durable antitumor effect and safety profile observed with abiraterone confirms earlier experience that it can be utilized long-term without significant concern for life-threatening toxicity.21,22
Taken together, these data strongly suggest that abiraterone merits consideration by clinicians as a new standard of care prior to chemotherapy in patients with mCRPC.
It has long been known that corticosteroids modulate mCRPC, and prednisone has been a comparator in randomized trials in the disease for decades.4,7,19
The present data, from a randomized phase 3 study, now validate this approach by demonstrating that targeting persistent extragonadal androgen synthesis26
leads to benefits that are superior to the standard prednisone comparator utilized in contemporary clinical trials. An additional notable finding is that the median OS of 27.2 months in the prednisone alone group is the longest survival prospectively observed in this patient population, possibly a consequence of anti-tumor activity of the prednisone control and impact of subsequent effective therapies.
In addition to a marked improvement in rPFS, treatment with abiraterone acetate was associated with a trend towards improved OS (HR, 0.75; P=0.009), accounting for a conservative allocation of α-level associated with an IA (Table 3 of the Supplementary Appendix
). Emblematic of the magnitude of the survival benefit of abiraterone acetate compared to prednisone are improvement trends in the OS of all pre-specified patient subgroups including older men and those with lower performance status, greater pain, and greater disease burden (). Despite the high disease burden and proportion of patients with Gleason score ≥8 enrolled, the survival curves did not separate until after approximately 12 months; an observation ascribed to the low number of events observed and active prednisone comparator, and consistent with a low rate of death in an asymptomatic or mildly symptomatic mCRPC population.
Those deaths that did occur early in the course of the study may result from the presence of a proportion of patients harboring a tumor phenotype against which androgen modulation may have little effect. Although the effectiveness of post-study therapies including abiraterone acetate is not known, the prevalence of subsequent therapy was higher in the prednisone group compared to the abiraterone group (60% versus 44%, respectively; Table 4 in the Supplementary Appendix
). The most common subsequent therapy was docetaxel in both groups.
The safety of abiraterone acetate observed in this study was similar to that previously reported in men with mCRPC and disease progression after docetaxel chemotherapy.19
Compared with prior studies, no toxicities unique to this patient population were identified despite a longer duration of abiraterone-prednisone treatment. Liver function abnormalities (typically seen in the first 3 months of therapy) and cardiac toxicities were more common in the abiraterone-treated patients. Cardiac abnormalities tended to appear later. Most toxicities were manageable, as discontinuation of abiraterone therapy due to toxicity was rare.
In summary, the totality of data accumulated in the present study—including the co-primary end points of rPFS and OS, the clinically meaningful secondary end points such as time to opiate use for cancer pain and time until chemotherapy, patient-reported outcomes related to delay in time to pain progression and degradation of HRQOL, and PSA and radiographic responses—support the use of abiraterone acetate as a new standard of care for patients with chemotherapy-naïve, asymptomatic or minimally symptomatic mCRPC.