September 24, 2021: “Positive high-level results from the PROpel Phase III trial showed AstraZeneca and MSD’s Lynparza (olaparib) in combination with abiraterone demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) versus standard-of-care abiraterone as a 1st-line treatment for men with metastatic castration-resistant prostate cancer (mCRPC) with or without homologous recombination repair (HRR) gene mutations.
At a planned interim analysis, the Independent Data Monitoring Committee (IDMC) concluded that the trial met the primary endpoint of rPFS in men with mCRPC who had not received treatment in the 1st-line setting including with new hormonal agents (NHAs) or chemotherapy.
The trial also showed a trend at this interim analysis towards improved overall survival (OS). However, the data are still immature and the trial will continue to assess OS as a key secondary endpoint.
The safety and tolerability were consistent with the known profiles of each medicine.
Prostate cancer is the second-most common cancer in men and despite an increase in the number of available treatments for men with mCRPC, five-year survival remains low.1
Susan Galbraith, Executive Vice President, Oncology R&D, said: “Today, men with metastatic castration-resistant prostate cancer have limited options in the 1st-line setting, and sadly often the disease progresses after initial treatment with current standards of care.
These exciting results demonstrate the potential for Lynparza with abiraterone to become a new 1st-line option for patients regardless of their biomarker status and reach a broad population of patients living with this aggressive disease. We look forward to discussing the results with global health authorities as soon as possible.”
Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: “We are encouraged by the PROpel results and the clinical benefit Lynparza in combination with abiraterone demonstrated versus abiraterone alone as a 1st-line treatment option for men with metastatic castration-resistant prostate cancer.
Today’s results build on MSD and AstraZeneca’s commitment to bring Lynparza earlier in lines of treatmentand to more patients with advanced prostate cancer.”
The data will be presented at an upcoming medical meeting.
Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant mortality rate. Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.
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.3 Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis.
Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.
Despite advances in treatment for men with mCRPC, five-year survival is low and extending survival remains a key treatment goal.
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 addition to abiraterone in men with mCRPC who had not received prior chemotherapy or NHAs in the 1st-line setting.
Men in both treatment groups will also receive either prednisone or prednisolone twice daily. The primary endpoint is rPFS and secondary endpoints include OS and time to first subsequent anticancer therapy or death.
The trial enrolled men with or without HRR gene mutations.
They may have previously been treated with docetaxel at a prior stage of disease. The trial excluded men with prior treatment with abiraterone. Treatment with any other NHA must have been stopped one year or longer prior to randomisation.
Men must have had a performance status of 0-1 as defined by the Eastern Cooperative Oncology Group (ECOG) criteria and be a candidate for abiraterone treatment with documented evidence of progressive disease.
Preclinical trials in prostate cancer report a combined anti-tumour effect when PARP inhibitors and NHAs are administered together.
PARP-1 is involved in the co-regulation of the androgen-receptor (AR) pathway, potentially leading to cooperation between PARP inhibitors and NHAs in blocking AR signalling.
PARP inhibition plus androgen deprivation could significantly reduce the growth of prostate cancer cells independent of HRR gene status. Other trials revealed that treatment with NHAs inhibit the transcription of some HRR genes, therefore, inducing HRR deficiency and increased sensitivity to PARP inhibitors via non-genetic mechanisms.
