In an analysis of the phase III PROfound trial reported in the Journal of Clinical Oncology, Joaquin Mateo, MD, PhD, and colleagues found that olaparib improved outcomes vs abiraterone or enzalutamide among the subgroup of patients with metastatic castration-resistant prostate cancer who had BRCA1/2 alterations.
The trial supported the May 2020 approval of olaparib in patients with homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer
Joaquin Mateo, MD, PhD
Study Details
In the open-label trial, 387 patients with HRR gene mutations (among 15 predefined genes) who had disease progression on a previous next-generation hormonal agent were randomly assigned 2:1 to receive olaparib at 300 mg twice a day or physician’s choice of enzalutamide at 160 mg once daily or abiraterone at 1,000 mg once daily plus prednisone at 5 mg twice a day. Among these patients, 160 had BRCA alterations, including 102 in the olaparib group and 58 in the control group. Overall, 128 patients had alterations in BRCA2 only, 13 in BRCA1 only, and 19 had BRCA1 and/or BRCA2 alterations plus alterations in another HRR gene. Patients in the control group were permitted to cross over to olaparib upon disease progression.
Key Findings
Among the 102 vs 58 patients with BRCA alterations, median radiographic progression–free survival was 9.8 months in the olaparib group vs 3.0 months in the control group (hazard ratio [HR] = 0.22, 95% confidence interval [CI] = 0.15–0.32). Median overall survival was 20.1 months vs 14.4 months (HR = 0.63, 95% CI = 0.42–0.95).
A total of 40 patients (69%) in the control group crossed over to olaparib after disease progression. Sensitivity analyses to adjust for crossover using rank-preserving structural failure time models showed that the hazard ratio for overall survival for olaparib vs control was between 0.27 (95% CI = 0.19–0.75) and 0.40 (95% CI = 0.27–0.90) depending on the model used.
Among 128 patients with BRCA2 alterations only, median radiographic progression–free survival was 10.8 months vs 3.5 months and the hazard ratio for overall survival was 0.59 (95% CI = 0.37–0.95). Among 13 patients with BRCA1 alterations only, median radiographic progression–free survival was 2.1 vs 1.8 months and the hazard ratio for overall survival was 0.42 (95% CI = 0.12–1.53).
Among patients evaluable for zygosity analysis, a radiographic progression–free survival benefit with olaparib was observed in all zygosity subgroups, including biallelic (n = 88; 11.4 vs 3.5 months, HR = 0.08, 95% CI = 0.04–0.16), heterozygous (n = 15; 4.7 vs 2.0 months, HR not applicable), and unknown (n = 57; 7.4 vs 3.0 months, HR = 0.30, 95% CI = 0.16–0.60).
Among 16 patients in the olaparib group with BRCA2 homozygous deletions, median radiographic progression–free survival was 16.6 months (95% CI = 9.3 months to not reached).
Among 112 patients undergoing germline DNA analysis, the hazard ratio for radiographic progression–free survival among 42 vs 19 patients with germline BRCA alterations was 0.08 (95% CI = 0.03–0.18), and the hazard ratio among 33 vs 18 patients with somatic alterations was 0.16 (95% CI = 0.07–0.37). Hazard ratios for overall survival were 0.55 (95% CI = 0.27–1.16) among patients with germline alterations and 0.66 (95% CI = 0.32–1.39) among those with somatic alterations.
The investigators concluded, “In all subgroups assessed, olaparib improved outcomes vs abiraterone or enzalutamide for patients with metastatic castration-resistant prostate cancer with BRCA alterations whose disease had progressed on previous next-generation hormonal agents.”
Dr. Mateo, of Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by AstraZeneca as part of an alliance between AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit ascopubs.org.
