On June 4, 2018 AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US (Merck: known as MSD outside the US and Canada) reported data, which showed clinical improvement in median radiologic progression-free survival (rPFS) with Lynparza (olaparib) in combination with abiraterone compared to abiraterone monotherapy, a standard of care, in metastatic castration-resistant prostate cancer (mCRPC) (Press release, AstraZeneca, JUN 4, 2018, View Source [SID1234527133]). Lynparza is being jointly developed and commercialised by AstraZeneca and MSD.

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The results of Study 08, a randomised, double-blinded, multi-centre Phase II trial, comparing Lynparza in combination with abiraterone (n=71) to abiraterone monotherapy (n=71) in patients with previously-treated mCRPC, regardless of homologous recombination repair (HRR) mutation status, were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, US, 1-5 June 2018 as a "Best of ASCO (Free ASCO Whitepaper) presentation" and were published online today in the Lancet Oncology. The primary endpoint was rPFS. Secondary endpoints included time to second progression or death (PFS2), overall survival (OS) and health-related quality of life.

Noel Clarke, Professor of Urological Oncology, Christie NHS Foundation Trust, Manchester, UK, said: "This is the first time we have seen an improvement with the use of a PARP inhibitor in combination with abiraterone in patients with metastatic castration-resistant prostate cancer and this effect may be independent of HRR status. The data suggest this therapeutic combination may be a promising new treatment approach for this aggressive disease."

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "A previous trial demonstrated improvements in response rates with Lynparza monotherapy in metastatic castration-resistant patients with HRR mutations. The Study 08 combination data suggests that regardless of their mutation status, men with metastatic castration-resistant prostate cancer may potentially benefit from Lynparza in combination with abiraterone."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "There is a significant unmet medical need for patients with metastatic castration-resistant prostate cancer as they are a high-risk group with limited treatment options. Lynparza is the first PARP inhibitor to demonstrate activity in combination with standard-of-care treatment in prostate cancer. These data from Study 08 represent another important milestone in the clinical development of Lynparza."

Median rPFS was 13.8 months with Lynparza and abiraterone compared to 8.2 months with abiraterone alone (HR 0.65; 95% CI 0.44-0.97; p=0.034). Median PFS2 was 23.3 months vs 18.5 months (HR 0.79; 95% CI 0.51–1.21). Median OS was 22.7 months with combination treatment versus 20.9 months with abiraterone alone (HR 0.91; 95% CI 0.60–1.38). Pre-specified exploratory subgroup analyses demonstrated an rPFS improvement in patients, regardless of HRR status (see Table 1). Study 08 was not powered for subgroup analyses, PFS2 and OS.

The safety profile of Lynparza and abiraterone was generally manageable, with no detrimental effect on quality of life compared to abiraterone alone. Grade ≥3 adverse events (AEs), serious AEs and treatment discontinuations due to AEs were more frequent with combination treatment than abiraterone alone (54% and 28%; 34% and 18%; 30% and 10%, respectively). The most common grade ≥3 AEs in the combination arm were anaemia (21%), pneumonia (6%) and myocardial infarction (6%). Serious cardiovascular events occurred in seven patients in the combination group and one patient in the abiraterone group.

In addition to Study 08, other studies are underway to explore the potential of Lynparza as a monotherapy for HRR-mutated mCRPC, including PROfound, which is testing Lynparza monotherapy vs. enzalutamide or abiraterone in patients with previously-untreated mCRPC. Additional trials are planned to explore Lynparza in combination for the treatment of mCRPC regardless of HRR status. Lynparza was granted Breakthrough Therapy Designation by the US Food and Drug Administration in 2016 for the treatment of BRCA-mutated or ATM-gene-mutated mCRPC.

Lynparza is a first-in-class PARP inhibitor approved for advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients. Lynparza has the broadest and most-advanced clinical trial development programme and AstraZeneca and MSD are working together to deliver Lynparza as quickly as possible to more patients across multiple cancer types, including prostate and pancreatic cancers.

NOTES TO EDITORS
About Study 08

Study 08 was a global, randomised, double-blinded, multi-centre Phase II trial of 142 patients, assessing the efficacy and safety of Lynparza tablets (300mg twice daily) and abiraterone tablets (4 x 250mg once daily) (n=71) compared to matched placebo and abiraterone tablets (4 x 250mg once daily) (n=71) in patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of HRR status. Prednisone/prednisolone (5mg BID) was administered to patients in both treatment arms.

Patients in Study 08 had previously received docetaxel for mCRPC. Prior to enrolment, patients had received no more than two lines of chemotherapy.

The primary endpoint was radiologic progression-free survival (rPFS) (time from randomisation to radiologic progression or death). rPFS is increasingly used in clinical trials of mCRPC as a clinically-meaningful endpoint focusing on the impact of treatment on the disease progression to areas where spread of prostate cancer is common, notably soft tissue and bone.

Secondary endpoints included time to second progression or death, overall survival and health-related quality of life.

About metastatic castration-resistant prostate cancer (mCRPC)

Prostate cancer is the second-most common cancer in men, with an estimated 1.6 million new cases diagnosed worldwide in 2015 and is associated with a significant mortality rate.[i] Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.[ii] mCRPC occurs when 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.ii Approximately 10-20% of men with advanced prostate cancer will develop CRPC within five years, and at least 84% of these will have metastases at the time of CRPC diagnosis.[iii] Of men with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.iii Despite an increase in the number of available therapies for men with mCRPC, five-year survival is only 28%.iii

About Lynparza

Lynparza (olaparib) was the first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Specifically, in vitro studies have shown that Lynparza-induced cytotoxicity may involve inhibition of PARP-enzymatic activity and increased formation of PARP-DNA complexes, resulting in DNA damage and cancer cell death.

Lynparza, which has the broadest clinical development programme of any PARP inhibitor, is being tested in a range of DDR-deficient tumour types, and is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.