US Regulatory Review of Lynparza/Abiraterone for Prostate Cancer

AstraZeneca and MSD today announced that the US Food and Drug Administration (FDA) will convene a meeting of the Oncologic Drugs Advisory Committee (ODAC) to discuss the supplemental new drug application (sNDA) for Lynparza (olaparib) in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC).

The ODAC meeting is scheduled for 28 April 2023. AstraZeneca and MSD are committed to working with the FDA to bring Lynparza in combination with abiraterone to patients with mCRPC.

The efficacy and safety of Lynparza in combination with abiraterone and prednisone or prednisolone have been demonstrated in the PROpel Phase III trial, first presented at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), and subsequently published in the New England Journal of Medicine Evidence. Further results from the final prespecified overall survival (OS) analysis were presented at ASCO GU 2023.

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.^1,2,3 In the United States, it is estimated that there will be 288,300 new cases and 34,700 deaths in 2023.⁴ Overall survival for patients with mCRPC is approximately three years in clinical trial settings, and even shorter in the real-world.⁵ 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.^6-11

Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant mortality rate.¹² Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.¹³

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.¹⁴ 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.¹⁴ Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.¹⁴

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.^14-17

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.^20-26 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 olaparib and AR activity with an NHA results in enhanced DNA damage and anti-tumour activity in non-HRRm prostate cancer models.^{21,24,26,27,28}