AstraZeneca's Olaparib Receives FDA Approval for First-Line Treatment of BRCA-Mutated mCRPC in Combination with Abiraterone and Prednisone/Prednisolone

On May 31, the FDA website showed that AstraZeneca's PARP inhibitor Olaparib (Lynparza) supplemental New Drug Application (sNDA) received FDA approval for use in combination with Abiraterone and Prednisone or Prednisolone as a first-line treatment for adult patients with BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC). This indication was approved in the EU in December 2022.

The FDA approval was based on the positive results of the Phase III PROpel study. This study was a multicenter, randomized, double-blind, placebo-controlled clinical trial (N=796) designed to evaluate the efficacy and safety of olaparib in combination with abiraterone and prednisone or prednisolone (N=399) compared to placebo in combination with abiraterone and prednisone or prednisolone (N=397) for the treatment of patients with mCRPC who have not previously received chemotherapy or new hormonal agent treatment, regardless of their homologous recombination repair gene mutation (HRRm) status.

The results showed that in the overall population, the median radiographic progression-free survival (rPFS) assessed by investigators was 24.8 months in the olaparib group and 16.6 months in the placebo group (HR=0.66; 95% CI: 0.54-0.81; P<0.001); the rPFS assessed by Blinded Independent Central Review (BICR) was 27.6 months in the olaparib group and 16.4 months in the placebo group (HR=0.61; 95% CI: 0.49-0.74).

Investigator-Assessed rPFS (Source: NEJM Evidence)

BICR-Assessed rPFS (Source: NEJM Evidence)

However, the situation in the HRRm subgroup population shows that mCRPC patients with HRRm benefit more significantly from olaparib combined with abiraterone and prednisone or prednisolone.

Note: A. In the HRRm subgroup, assessed by the investigator; B. In the HRRm subgroup, assessed by BICR;

C. Non-HRRm subgroup, investigator assessment; D. Non-HRRm subgroup, BICR assessment.

Moreover, the combination of olaparib with abiraterone and prednisone or prednisolone demonstrated good safety and tolerability. The most common (incidence ≥20%) adverse events (AEs) were anemia (49.7%), fatigue (38.7%), nausea (30.7%), back pain (21.6%), and diarrhea (20.6%).

At the ASCO GU 2023 conference, AstraZeneca announced the OS results of the study. In the intent-to-treat population, the OS was 42.1 months for the olaparib plus abiraterone and prednisone or prednisolone group, and 34.7 months for the placebo group (maturity 47.9%; HR=0.81; 95% CI: 0.67-1.00; P=0.0544), with no significant difference.

At the Oncologic Drugs Advisory Committee (ODAC) meeting held on April 28, 2023, the FDA expert panel voted 11:1 that the applicable population for this combination therapy should be restricted to mCRPC patients with BRCAm (see: ). Ultimately, the FDA also accepted ODAC's recommendation.

Olaparib is a PARP1/2 inhibitor independently developed by AstraZeneca. It is the world's first marketed PARP inhibitor and also the first targeted therapy drug to utilize defects in the DNA damage repair pathway to kill cancer cells. In July 2017, AstraZeneca entered into a strategic collaboration agreement with Merck to jointly develop and commercialize Olaparib as a monotherapy and combination therapy.

In December 2014, Olaparib was first approved for marketing in the European Union (EU) as a first-line maintenance treatment for patients with platinum-sensitive recurrent BRCA-mutated (germline and/or somatic) high-grade serous epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who had achieved complete or partial response to platinum-based chemotherapy. As of today, Olaparib has been approved for nine indications, one of which was withdrawn in August 2022 (see: ).

Indications for Olaparib Approved in the United States

In the United States, prostate cancer is the second most common cancer among male patients. It is estimated that approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these patients may have metastases at the time of CRPC diagnosis. In clinical trials, the overall survival period for mCRPC patients is about three years, and even shorter in real-world settings.

Currently, there are three PARP inhibitors globally approved for the mCRPC indication, the other two being Rubraca (rucaparib, Clovis Oncology) and Akeega (niraparib acetate abiraterone compound, Johnson & Johnson). However, olaparib is the only PARP inhibitor that has gained approval for both first-line and second-line mCRPC indications.

In addition to the three marketed PARP inhibitors, Pfizer's talazoparib has also been submitted for regulatory approval in the United States for the first-line treatment of mCRPC, offering patients with mCRPC potentially more first-line treatment options.

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