AstraZeneca and Merck Announce Positive Phase 3 PROpel Trial Results for Lynparza in First-Line mCRPC

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On September 24, AstraZeneca and MSD announced the interim analysis results from the Phase 3 PROpel trial. The data demonstrated that, regardless of homologous recombination repair (HRR) gene mutation status, treatment with Lynparza (olaparib) in combination with Zytiga (abiraterone) resulted in a statistically and clinically significant improvement in the primary endpoint of radiographic progression-free survival (rPFS) compared with Zytiga alone for the first-line treatment of metastatic castration-resistant prostate cancer (mCRPC). A trend toward improvement was also observed for the key secondary endpoint of overall survival (OS), although the OS data were not yet mature at the time of the interim analysis.

Lynparza is a PARP inhibitor that received US FDA approval in May 2020 for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations whose disease has progressed following prior novel hormonal therapy with Zytiga or Xtandi (enzalutamide). HRR gene mutations account for approximately 20–30% of mCRPC cases. Zytiga and Xtandi are blockbuster prostate cancer drugs from Johnson & Johnson and Pfizer/Astellas, respectively, and serve as the standard-of-care first-line therapies for mCRPC.

Notably, Lynparza is the first PARP inhibitor to demonstrate clinical benefit in the first-line treatment of prostate cancer. The highly positive results from the PROpel trial are expected to open up a broader market for Lynparza. Although the data are not yet mature, AstraZeneca and MSD have already planned to submit them to regulatory authorities for review.

First-line treatment options for mCRPC are limited, and many patients experience disease progression following current standard-of-care regimens. The combination of Lynparza and Zytiga has the potential to provide a new first-line treatment option for the mCRPC patient population, regardless of biomarker status.

Currently, competition for PARP inhibitors as first-line therapy for prostate cancer is intensifying. Johnson & Johnson is also evaluating the PARP inhibitor niraparib in combination with Zytiga and prednisone as a first-line regimen for patients with mCRPC, including those with or without homologous recombination repair (HRR) pathway gene alterations, in the Phase 3 MAGNITUDE trial.

In May last year, the US FDA also approved Clovis Oncology's PARP inhibitor Rubraca for third-line treatment of BRCA-mutation-positive mCRPC. BRCA mutations are a type of homologous recombination repair (HRR) pathway deficiency. Recently, a Phase 3 clinical trial is evaluating Rubraca in combination with Xtandi as first-line treatment for mCRPC, compared with Xtandi monotherapy.

Pfizer is also evaluating the combination of Talzenna and Xtandi as first-line treatment for prostate cancer in the Phase 3 TALAPRO-2 trial. Talzenna is also a PARP inhibitor approved only for the treatment of BRCA-mutated breast cancer.

Currently, Lynparza maintains a leading position in the PARP inhibitor class, with sales reaching $1.13 billion in the first half of 2021, a 15% year-on-year increase. Following its recent success in the first-line treatment of mCRPC and positive data for the adjuvant treatment of high-risk early breast cancer, Lynparza is expected to achieve further robust growth in the future. Additionally, despite competition from generic drugs and novel therapies, Zytiga has also delivered impressive performance, with global sales reaching $1.2 billion in the first half of this year.

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