Adding abiraterone acetate and prednisone to enzalutamide demonstrated in the Alliance A031201 study that such a strategy does not significantly prolong overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting. The results related to study secondary endpoints also do not support combination therapy. Although radiographic progression-free survival (rPFS) was 3 months longer in the combination arm, and although this difference was statistically significant, it is of limited clinical meaningfulness, given the added toxicities and costs. Rates of prostate specific antigen (PSA) declines were also not different between the two arms.
The combination was associated with an unfavourable drug-drug interaction that increased abiraterone acetate clearance and with more adverse events. The combination of enzalutamide plus abiraterone acetate and prednisone is currently not recommended in routine clinical practice. The study findings are published by Dr. Michael J. Morris of the Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center in New York, NY, US, and colleagues on 30 March 2023 in the Journal of Clinical Oncology.
The authors wrote in the background that discovery that the androgen receptor actively signals despite androgen-deprivation therapy transformed the treatment of mCRPC. The mechanisms of action of enzalutamide and abiraterone acetate are different, and each is well suited to address the resistance mechanisms associated with the other. A phase I study demonstrated that the combination of abiraterone acetate and enzalutamide was safe, did not appear to result in altered pharmacokinetics, and yielded favourable PSA response rates and PFS.
The Alliance A031201 study team hypothesised that the addition of abiraterone acetate and prednisone to enzalutamide for first-line treatment of mCRPC, compared with enzalutamide alone, would result in prolonged rPFS and OS. They further hypothesised that there would be no drug-drug interactions according to the previous phase I data. The study team sought to confirm the association of rPFS with OS as observed in the registration studies for abiraterone acetate and enzalutamide and, as a post hoc analysis, examined whether expanding the definition of progression to include clinical progression and/or post-treatment radiographic progression would identify a stronger association between rPFS and OS.
In the Alliance A031201, men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without abiraterone acetate and prednisone. The primary endpoint was OS. Toxicity, PSA declines, pharmacokinetics, and rPFS were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments.
In total, 1311 patients were randomly assigned, 657 to enzalutamide and 654 to enzalutamide plus abiraterone acetate and prednisone. OS was not statistically different between the two arms with median OS of 32.7 months for enzalutamide versus 34.2 months for enzalutamide plus abiraterone acetate and prednisone (hazard ratio [HR] 0.89; one-sided p = 0.03; boundary nominal significance level = 0.02).
rPFS was longer in the combination arm with median rPFS of 21.3 months for enzalutamide versus 24.3 months for enzalutamide plus abiraterone acetate and prednisone (HR 0.86; two-sided p = 0.02). However, pharmacokinetic clearance of abiraterone acetate was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone acetate alone.
In both study arms, the treatment was well tolerated by most patients, given the low rate of grade 3 or higher toxicities. However, the incidences of high-grade non-haematological toxicity (69% versus 55%), fatigue (11% versus 6%), hypertension (31% versus 22%), all-grade atrial fibrillation (2% versus 1%), and transaminitis (43% versus 19%) were higher in the combination arm, consistent with the known side-effect profile of abiraterone acetate. The incidence of all-grade arthralgia (45% versus 36%) was higher in the enzalutamide arm, perhaps because of the use of prednisone with abiraterone acetate. The incidence of seizure was similar between the arms, <1% in each arm.
The authors commented that one possible reason for the lack of effect of the combination approach is the apparent effect of enzalutamide on hepatic clearance of abiraterone acetate. The results suggest that enzalutamide induces abiraterone acetate metabolism, similar to other CYP3A4 inducers. Although this drug–drug interaction may have limited the efficacy of the combination, toxicities were still significantly higher, suggesting that further dose escalation of abiraterone acetate may not be well tolerated or acceptable, and only a dedicated dose-escalation study of higher doses of abiraterone acetate given with enzalutamide could address this.
The authors concluded that this was an adequately designed, NCI-funded, randomised phase III study with the gold standard primary endpoint of OS. However, the results demonstrate that such a strategy does not significantly prolong OS in first-line treatment of mCRPC.
The study was previously presented in part at the ASCO 2019 Annual Meeting in Chicago, IL, US (31 May-4 June).
The study was supported by the awards of the US National Cancer Institute to the Alliance for Clinical Trials in Oncology, Memorial Sloan Kettering Cancer Center, SWOG, and to University of Pittsburgh. It was also supported in part by funds from Astellas.
Reference
Morris MJ, Heller G, Hillman DW, et al. Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial). JCO; Published online 30 March 2023. DOI: 10.1200/JCO.22.02394