The Food and Drug Administration's (FDA) Oncologic Drugs Advisory Committee (ODAC) has recognised a favourable benefit risk profile for AstraZeneca and MSD's Lynparza (olaparib) plus abiraterone and prednisone or prednisolone for the treatment of adult patients with BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC) based on the PROpel Phase III trial. The Committee voted 11 to 1, with 1 abstaining, that the indication should be limited to patients whose tumours have a BRCA mutation.
In August 2022, the FDA accepted the supplemental New Drug Application (sNDA) for Lynparza based on positive results from the pivotal PROpel trial, also published in NEJM Evidence. The ODAC provides the FDA with independent, expert advice and recommendations on marketed and investigational medicines for use in the treatment of cancer. The FDA is not bound by the Committee's guidance but takes its advice into consideration. AstraZeneca and MSD will continue to work with the FDA as it completes its review of the application.
Neal Shore, Chief Medical Officer of Urology and Surgical Oncology for Genesis Care, US and PROpel trial investigator, said: "Today's recommendation by the ODAC is disappointing news for clinicians and prostate cancer patients alike. Preventing or delaying radiographic progression is an important clinical endpoint in assessing oncologic treatment and is very relevant to patients, their caregivers and their families. It is essential that physicians and patients have an opportunity to choose treatment with the goal of optimising cancer care outcomes."
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said: "Novel treatment options are urgently needed for patients with metastatic castration-resistant prostate cancer. While we are pleased with the recognition of the benefit of Lynparza plus abiraterone for patients with BRCA-mutated metastatic castration-resistant prostate cancer, we are disappointed with the outcome of today's ODAC meeting. We strongly believe in the results of the PROpel trial, which demonstrated the clinically meaningful benefit for this combination in a broad population of patients regardless of biomarker status."
Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer, MSD Research Laboratories, said "With the incidence and mortality of prostate cancer set to double in the coming decades, it is critical that we bring new treatment options with the potential to reduce the risk of disease progression or death to patients at the earliest possible moment in their care. While we are pleased that the ODAC recommended Lynparza for patients with metastatic castration-resistant prostate cancer who have BRCA mutations, we believe in the potential of Lynparza plus abiraterone for a broad range of patients with metastatic castration-resistant prostate cancer, based on the results of PROpel. We look forward to the outcome of the FDA's review of the application."
Results from the PROpel trial showed a statistically significant and clinically meaningful 34% reduction in the risk of radiographic disease progression or death with Lynparza plus abiraterone with prednisone or prednisolone, versus abiraterone alone in patients with mCRPC (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.54-0.81; p1
Further results from the final prespecified overall survival (OS) analysis presented at ASCO Genitourinary Cancers Symposium 2023 showed Lynparza plus abiraterone and prednisone or prednisolone demonstrated median OS of 42.1 months versus 34.7 months for abiraterone plus placebo. This result represents a 7.4-month absolute difference in median OS versus a standard of care (47.9% maturity, HR of 0.81, 95% CI 0.67-1.00; p=0.0544). While this numerical increase in median OS did not achieve statistical significance, it builds on the meaningful survival gains achieved for patients in this setting treated with abiraterone alone, a current standard of care.
In exploratory analyses of the BRCAm subgroup, Lynparza plus abiraterone demonstrated improvements in both rPFS (HR of 0.23, 95% CI, 0.12-0.43) and OS (HR of 0.29, 95% CI, 0.14-0.56). In the non-BRCAm subgroup, Lynparza plus abiraterone also showed improvements in rPFS (HR of 0.76, 95% CI, 0.61-0.94), and a modest trend for OS (HR of 0.91, 95% CI, 0.73-1.13).
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 EU and several other countries for the treatment of adult patients with mCRPC based on the PROpel trial.
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 2020.2-4 In the United States, it is estimated that there will be 288,300 new cases and 34,700 deaths in 2023.5 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 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 the PROpel Phase III trial, Lynparza is combined with abiraterone, an NHA which targets the androgen receptor (AR) pathway. AR signalling engages a transcriptional programme that is critical for tumour cell growth and survival in prostate cancer.18,19 In addition, the AR also plays a role in repairing DNA damage in prostate cancer cells, including damage not normally repaired by homologous recombination repair (HRR). Preclinical models have suggested a number of potential mechanisms that could account for increased combination efficacy in both HRR deficient and HRR proficient prostate cancer.1,19-25 Recent data provide evidence that PARP facilitates AR-DNA binding in the presence of DNA damage (AZ internal data on file) and that combined inhibition of PARP with Lynparza and AR activity with an NHA results in enhanced DNA damage and anti-tumour activity in non-HRRm prostate cancer models.1,21,24,26,27
