PUBLISHED24 August 2023
Approval based on PROpel Phase III trial results which showed Lynparza combination
reduced the risk of disease progression or death by 77% vs. abiraterone alone
First PARP inhibitor approved in Japan to demonstrate clinically
meaningful benefits in combination with a new hormonal agent
AstraZeneca and MSD’s Lynparza (olaparib) in combination with abiraterone and prednisolone has been approved in Japan for the treatment of adult patients with BRCA-mutated (BRCAm) castration-resistant prostate cancer with distant metastasis (mCRPC).
This approval by the Japanese Ministry of Health, Labour and Welfare was based on a subgroup analysis of the PROpel Phase III trial which showed that Lynparza plus abiraterone demonstrated highly clinically meaningful improvements in both radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone alone in patients with BRCA mutations.
Prostate cancer is the most common cancer in men in Japan and the sixth leading cause of cancer death in the region.1 Despite various treatment options available, the prognosis for mCRPC remains poor, with limited options for patients whose cancer progresses following initial treatment.1,2
Mototsugu Oya, Professor and Chairman, Department of Urology, Keio University School of Medicine, Japan, said: “The PROpel trial showed that the combination of Lynparza plus abiraterone delivered clinically meaningful improvements in outcomes for patients with BRCA-mutated metastatic castration-resistant prostate cancer. 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.”
Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “This Lynparza 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. 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.”
Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer, MSD Research Laboratories, said: “Prostate cancer impacts thousands of patients in Japan each year, and currently there are limited options available to those with metastatic disease. 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.”
In the subgroup analysis of PROpel, results showed that Lynparza plus abiraterone reduced the risk of disease progression or death by 77% (based on a hazard ratio [HR] of 0.23; 95% confidence interval [CI] 0.12-0.43) and reduced the risk of death by 61% (based on a HR of 0.39; 95% CI 0.16-0.86) versus abiraterone alone in patients with BRCAm mCRPC. Median rPFS and median OS were not reached for patients treated with Lynparza plus abiraterone versus a median of 8.4 months and 23.6 months, respectively, for those treated with abiraterone alone.
The safety and tolerability of Lynparza plus abiraterone in PROpel was in line with that observed in prior clinical trials and the known profiles of the individual medicines.
Lynparza in combination with abiraterone and prednisone or prednisolone is approved in the European Union (EU) and several other countries for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated, based on the PROpel trial. This combination is also approved in the US for the treatment of adult patients with deleterious or suspected deleterious BRCAm mCRPC.
Lynparza monotherapy is also approved in Japan for patients with BRCAm mCRPC based on results from the PROfound Phase III trial. It is approved in the EU and China for the same indication, as well as in the US for patients with homologous recombination repair (HRR) gene-mutated mCRPC (BRCA and other HRR gene mutations) who have progressed following prior treatment with enzalutamide or abiraterone.
Notes
Prostate cancer
Prostate cancer is the second most commonly diagnosed cancer in men and the fifth leading cause of cancer death in men globally, with an incidence of 1.4 million and 375,000 deaths in 2020.3,4 In Japan, there are an estimated 96,400 new cases and 13,300 deaths in 2022.2,5 Overall survival for patients with mCRPC is approximately three years in clinical trial settings, and even shorter in the real-world.6 Approximately half of patients with mCRPC may receive only one line of active treatment, and those that go on to receive further treatment often have diminishing benefit of subsequent therapies.7-12
Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant mortality rate.13 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.14
In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body despite the use of androgen-deprivation therapy to block the action of male sex hormones.15 Approximately 10-20% of men with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis.16 Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.16
Despite the advances in mCRPC treatment in the past decade with taxane and new hormonal agent (NHA) treatment, there is a high unmet need in this population.15-18
PROpel
PROpel is a randomised, double-blind, multi-centre Phase III trial testing the efficacy, safety, and tolerability of Lynparza versus placebo when given in combination with abiraterone, as well as prednisone or prednisolone, in men with mCRPC who had not received prior chemotherapy or NHAs in the mCRPC setting.
The primary endpoint is rPFS and secondary endpoints include OS, time to secondary progression or death, and time to first subsequent therapy. In September 2021, at a planned interim analysis, the Independent Data Monitoring Committee concluded that the PROpel trial met the primary endpoint of rPFS.
For more information about the trial please visit ClinicalTrials.gov.
Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in HRR, such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as NHAs).
Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death.
Lynparza is currently approved in a number of countries across multiple tumour types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination repair deficient (HRD)-positive advanced ovarian cancer, respectively; for germline BRCA mutation (gBRCAm), HER2-negative metastatic breast cancer (in the EU and Japan this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; in combination with abiraterone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated (EU) and for BRCAm mCRPC (US); and as monotherapy for HRR gene-mutated mCRPC in patients who have progressed on prior NHA treatment (BRCAm only in the EU and Japan). In China, Lynparza is approved for the treatment of BRCAm mCRPC as well as a 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovarian cancer.
Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 75,000 patients worldwide. Lynparza has a broad clinical trial development programme, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.
The AstraZeneca and MSD strategic oncology collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase inhibitor, for multiple cancer types.
Working together, the companies will develop Lynparza and Koselugo and other potential new medicines as monotherapies and as combinations. The companies will also develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines independently.
AstraZeneca in oncology
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AstraZeneca
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