European Commission Approves Olaparib Plus Abiraterone and Prednisone/Prednisolone for mCRPC

The European Commission (EC) has approved the combination of olaparib (Lynparza) plus abiraterone acetate (Zytiga) and prednisone or prednisolone for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated.¹

The approval was based on a positive recommendation from the Committee for Medicinal Products for Human Use and supported by data from the phase 3 PROpel trial (NCT03732820).

Findings from the study showed that the combination reduced the risk of disease progression or death by 34% compared with placebo plus abiraterone and prednisone or prednisolone (HR, 0.66; 95% CI, 0.54-0.81; P <.001).² Patients in the experimental arm experienced a median radiographic progression-free survival (rPFS) of 24.8 months (95% CI, 20.5-27.6) compared with 16.6 months (95% CI, 13.9-19.2) for those in the placebo arm, per investigator assessment. The median rPFS per blinded independent central review assessment was 27.6 months and 16.4 months for the olaparib and placebo arms, respectively.

“The results of the PROpel phase 3 trial of olaparib in combination with abiraterone as a first-line treatment show that this therapeutic combination can provide significant clinical benefit to patients with mCRPC. Patients with this condition in the European Union will now, for the first time, have the opportunity to benefit from this new treatment combination,” Noel Clarke, MBBS, FRCS, ChM, urological surgeon and professor of urological oncology at Manchester’s Christie/Salford Royal Hospitals and Manchester University, and a senior investigator of the PROpel trial, stated in a press release.

The double-blind PROpel trial enrolled patients with mCRPC irrespective of homologous recombination repair mutation status. Patients were required to be at least 18 years of age with histologically or cytologically confirmed prostate adenocarcinoma; have first-line mCRPC; be a candidate for abiraterone therapy with documented evidence of progressive disease; have an ECOG performance status of 0 or 1; have adequate organ and bone marrow function; and have a life expectancy of at least 6 months.³

Key exclusion criteria included myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML; clinically significant cardiovascular disease; planned or scheduled cardiac surgery or percutaneous coronary intervention procedure; prior revascularization procedure; uncontrolled hypertension; or history of uncontrolled pituitary or adrenal dysfunction.

Patients were randomly assigned 1:1 to receive 300 mg of olaparib or placebo twice daily in combination with 1000 mg of abiraterone once daily and prednisone or prednisolone.

The primary end point of the trial was rPFS. Key secondary end points included overall survival (OS), time to first subsequent anticancer therapy or death, time to pain progression, time to second progression or death, and health-related quality of life. Exploratory end points included objective response rate, prostate-specific antigen (PSA) response rate, and time to PSA progression.

Additional data showed that interim results for OS did not reach statistical significance, with an event rate of 37.1% in the experimental arm compared with 43.1% in the placebo arm (HR, 0.83; 95% CI, 0.66-1.03).

Regarding safety, findings were generally consistent with the known individual toxicity profiles for olaparib, abiraterone, and prednisone or prednisolone. Approximately 16% of patients in the olaparib arm discontinued treatment due to an adverse effect (AE). The most common any-grade AEs occurring in at least 20% of patients in the experimental arm included anemia (46%), fatigue (37%), and nausea (28%). Grade 3 or higher AEs consisted of anemia (15%), hypertension (4%), urinary tract infection (2%), fatigue (2%), decreased appetite (1%), vomiting (1%), back pain (1%), diarrhea (1%), and nausea (0.3%)

On December 15, 2022, the FDA informed AstraZeneca and MSD that the agency will extend the Prescription Drug User Fee Act date by 3 months to provide further time for a full review of the supplementary new drug application (sNDA) for olaparib plus abiraterone and prednisone or prednisolone for the treatment of patients with mCRPC.⁴ The FDA granted a priority review to the sNDA in August 2022.⁵

References

1. Lynparza® (olaparib) in combination with abiraterone and prednisone or prednisolone approved in the EU as treatment for certain patients with metastatic castration-resistant prostate cancer. News release. AstraZeneca and Merck. December 21, 2022. Accessed December 21, 2022. https://bit.ly/3GanUUY
2. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evidence. Published online June 3, 2022. doi:10.1056/EVIDoa2200043
3. Study on olaparib plus abiraterone as first-line therapy in men with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated April 5, 2022. Accessed December 21, 2022. https://clinicaltrials.gov/ct2/show/NCT03732820
4. Update on US regulatory priority review of Lynparza in combination with abiraterone in metastatic castration-resistant prostate cancer. News release. AstraZeneca. December 15, 2022. Accessed December 21, 2022. https://bit.ly/3hrYecK
5. Lynparza in combination with abiraterone granted priority review in the US for patients with metastatic castration-resistant prostate cancer. News release. AstraZeneca. August 16, 2022. Accessed December 21, 2022. https://bit.ly/3Pw4Lhs