‘More Is Not Better’ in Metastatic Castration-Resistant Prostate Cancer

CHICAGO-Combination therapy with enzalutamide, abiraterone, and prednisone did not prolong overall survival in men with metastatic castration-resistant prostate cancer (CRPC) compared with enzalutamide alone.

The results of the Alliance A031201 study (abstract 5008) were presented by Michael J. Morris, MD, of Memorial Sloan Kettering Cancer Center in New York, at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 31–June 4 in Chicago.

When androgen receptor agonists are used for the treatment of metastatic CRPC, compensatory mechanisms can limit the anti-androgen activity. Therefore, the Alliance A031201 investigators hypothesized that combining the anti-androgen enzalutamide with the androgen biosynthesis inhibitor abiraterone to prevent androgen compensation would prolong survival. The primary endpoint was overall survival (OS).

“Secondarily, this was the third of a preplanned series of prospective studies to qualify radiographic progression–free survival (rPFS) as a regulatory outcome measure sufficient for new drug approval and, therefore, we examined the relationship of rPFS and OS,” said Morris.

The phase III trial included patients with progressive metastatic CRPC who had not received prior treatment with taxanes or enzalutamide, abiraterone, and prednisone; however, chemotherapy was allowed for nonmetastatic prostate cancer that had progressed. In total, 1,311 patients were randomized to receive enzalutamide (n = 657) or enzalutamide plus abiraterone and prednisone (n = 654). Randomization was stratified by prior chemotherapy and Halabi prognostic three risk groups, factors which were adjusted for in the primary analysis.

Of the 1,311 patients, 15.6% were high risk, 35.3% were intermediate risk, and 48.1% were low risk. The median OS was 33.6 months (95% CI, 30.5–36.4 months) for the enzalutamide group and 32.7 months (95% CI, 29.9–35.4 months) for the enzalutamide/abiraterone/prednisone group (P = .53). A 50% decline rate in prostate-specific antigen levels was 80% for patients on enzalutamide plus abiraterone and prednisone and 76.5% for those taking enzalutamide alone. 

“There’s simply not that much more anticancer activity in one arm vs another,” said Morris.

The investigators continued to image the patients post-treatment if the patients ended treatment for nonradiographic progression–related reasons, providing on-treatment and off-treatment rPFS. Overall, rPFS was not different between the on- and off-treatment groups; however, to qualify rPFS as a regulatory biomarker for drug approval, the correlation between on-treatment rPFS and OS (Kendall’s tau), which represents a per-patient level analysis, was strong, at 0.70 (95% CI, 0.67–0.72), meaning that “the faster a patient progresses, the shorter his life,” noted Morris.

Progression or death occurred in 48% of patients taking enzalutamide/abiraterone/prednisone and 57% of patients taking enzalutamide alone. The primary reason for discontinuing treatment was radiographic progression (enzalutamide, 42% vs combination, 33%).

Grade 3–5 adverse events occurred in 55.6% and 68.8% of patients taking enzalutamide and enzalutamide/abiraterone/prednisone, respectively. Treatment discontinuation (12% vs 5%) and patient withdrawal rates (13% vs 5%) were higher in the combination group due to adverse events.

“The Alliance study shows that more is not better in first-line metastatic therapy,” said Michael Carducci, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins, who was the discussant for the study.