The Japanese Ministry of Health, Labour, and Welfare has approved the combination of olaparib plus abiraterone acetate and prednisone or prednisolone for the treatment of adult patients with BRCA-mutated castration-resistant prostate cancer with distant metastasis.
The Japanese Ministry of Health, Labour, and Welfare has approved the combination of olaparib (Lynparza) plus abiraterone acetate (Zytiga) and prednisone or prednisolone for the treatment of adult patients with BRCA-mutated castration-resistant prostate cancer (mCRPC) with distant metastasis.1
The approval is based on findings from a subgroup analysis of the phase 3 PROpel trial (NCT03732820), in which the combination reduced the risk of progression or death by 77% (HR, 0.23; 95% CI, 0.12-0.43) and reduced the risk of death by 61% (HR, 0.39; 95% CI, 0.16-0.86) vs abiraterone acetate alone in patients harboring BRCA mutations (n = 85).1 The median radiographic progression-free survival (rPFS) and overall survival (OS) were not reached for patients in this population who received the combination vs 8.4 months and 23.6 months, respectively, in those who received abiraterone acetate alone.
Additionally, the safety profile of the combination was similar to that seen in prior clinical trials and the established adverse effects (AEs) of each agent alone.
“The PROpel trial showed that the combination of [olaparib] plus abiraterone delivered clinically meaningful improvements in outcomes for patients with BRCA-mutated metastatic castration-resistant prostate cancer,” Mototsugu Oya, professor and chairman, Department of Urology, Keio University School of Medicine in Japan, stated in a news release. “With this approval, patients in Japan will now have the opportunity to benefit from this new treatment combination which has the potential to become the new standard of care for patients with BRCA mutations.”
The combination is also approved in the United States for patients with deleterious or suspected deleterious BRCA-mutant mCRPC2 and in the European Union and other countries for all-comers with mCRPC in whom chemotherapy is not clinically indicated.1
PROpel is a randomized, double-blind, placebo-controlled, multicenter trial that enrolled patients at least 18 years of age with histologically or cytologically confirmed prostate adenocarcinoma who had at least 1 documented metastatic lesion on bone, computed tomography, or magnetic resonance imaging scan. Prior treatment with next-generation hormonal agents and prior chemotherapy in the metastatic castration-resistant setting precluded enrollment, although prior docetaxel for localized or metastatic hormone-sensitive prostate cancer was allowed.3
A total of 796 patients were randomly assigned to receive 300 mg of olaparib twice daily plus 1000 mg of abiraterone daily (n = 399) or placebo plus abiraterone (n = 397). All patients received 5 mg of prednisone or prednisolone twice daily plus a gonadotropin-releasing hormone analog or prior bilateral orchiectomy. Treatment with olaparib was continued until radiographic progression or intolerable toxicity.
rPFS by RECIST v1.1 and Prostate Cancer Working Group criteria served as the trial’s primary end point. Secondary end points included OS, time to first subsequent anticancer therapy or death (TFST), time to pain progression, symptomatic skeletal-related events, second progression or death (PFS2), opiate use, and quality of life.
Findings from the trial’s final OS analysis presented at the 2023 ASCO Genitourinary Cancers Symposium demonstrated a numerical but not statistically significant improvement in OS in the intention-to-treat population (HR, 0.81; 95% CI, 0.67-1.00; P =.0544). A trend toward OS benefit was also seen in the homologous recombination repair–mutant (HR, 0.66; 95% CI, 0.45-0.95) and non-mutant populations (HR, 0.89; 95% CI, 0.70-1.14).4,5 Consistent benefit was also seen in TFST (HR, 0.76; 95% CI, 0.64-0.90) and PFS2 (HR, 0.76; 95% CI, 0.59-0.99).
“This [olaparib] combination has been shown to reduce the risk of disease progression or death compared to standard of care and underscores the critical importance of BRCA testing at metastatic diagnosis,” Dave Fredrickson, executive vice president, Oncology Business Unit, AstraZeneca, stated in the release.1 “Today’s approval is a major step forward for patients in Japan with BRCA-mutated metastatic castration-resistant prostate cancer who urgently need new first-line treatment options.”
The most common AEs experienced by more than 10% of patients in the combination arm included anemia (any grade, 49.7%; grade ≥3, 16.1%), fatigue or asthenia (38.7%; 2.5%), nausea (30.7%; 0.3%), back pain (21.6%; 1%), diarrhea (20.6%; 1.3%), constipation (18.6%; 0%), decreased appetite (16.6%; 1%), and vomiting (15.6%; 1.5%). Notably, health-related quality of life was similar between arms, with least-square mean changes from baseline of –5.84 with the combination and –5.30 with placebo (HR, 0.54; 95% CI, –3.00 to 1.92).5
“Prostate cancer impacts thousands of patients in Japan each year, and currently there are limited options available to those with metastatic disease,” Eliav Barr, senior vice president, head of Global Clinical Development and chief medical officer, MSD Research Laboratories, added in the release.1 “It is very important to develop and deliver novel treatment combinations to patients with BRCA-mutated metastatic castration-resistant prostate cancer that improve on the current standard of care.”