Olaparib Combination Shows Increased Median Overall Survival in Fatal Metastatic Prostate Cancer

Olaparib (Lynparza; AstraZeneca, Merck & Co.) with abiraterone and prednisone, or the combination of olaparib and prednisolone, was found to increase overall survival (OS) in male patients with metastatic castration-resistant prostate cancer (mCRPC), according to data presented at the 2023 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium.

CRPC can affect up to 20% of men with advanced prostate cancer, and at least 84% will have metastases at the time of diagnosis—the disease is associated with a significant mortality rate.

“From the primary radiographic progression-free survival analysis (rPFS) presented at ASCO GU last year to the updated [OS] data presented today, the data reinforce the therapeutic potential of olaparib plus abiraterone and prednisone for patients with metastatic castration-resistant prostate cancer (mCRPC) in the overall trial population and across subgroups,” said senior investigator Noel Clarke, urological surgeon and professor of Urological Oncology at Manchester’s Christie/Salford Royal Hospitals and Manchester University, in a press release.

There were 1.4 million men diagnosed with prostate cancer in 2020. Patient mortality rate is also expected to double in the next 2 decades, said Eliav Barr, head, Global Clinical Development and chief nedical officer, Merck & Co, Inc. Research Laboratories, in the press release.

Olaparib is a poly-adenosine diphosphate-ribose polymerase (PARP) inhibitor that blocks the DNA damage response (DDR) in homologous recombination repair (HRR)-deficient cells and tumors, such as mCRPC. Abiraterone is a new hormonal agent (NHA) that targets the androgen receptor (AR) pathway. Previous data support the combination of a PARP inhibitor (oliparib) with an NHA for increased anti-tumor activity in non-HRRm prostate cancers.

Investigators studied the efficacy, safety, and tolerability of olaparib against placebo (abiraterone alone) for male patients with mCRPC who have not received chemotherapy or NHAs in the randomized, double-blind, multi-center, phase 3 PROpel trial. The team tested olaparib as a combination therapy with abiraterone and prednisone or prednisolone. The primary endpoint was rPFS, and secondary endpoints of OS, time to secondary progression or death, and time until next therapy.

Olaparib and abiraterone reduced risk of disease progression by 34% compared to abiraterone alone. In addition, olaparib with abiraterone and prednisone (and olaparib and prednisolone) increased median OS by 7.4 months (42.1 versus 34.7 months) compared to placebo.

“The results in the overall trial population from PROpel illustrate how the combination of olaparib and abiraterone can exploit the dependency of the androgen receptor’s role in DNA repair on PARP to provide greater anticancer activity than abiraterone alone,” said Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, in the press release.

Nearly half of patients taking olaparib with abiraterone experienced anemia (49.7%). Other common adverse events (AEs) included fatigue (38.7%), nausea (30.7%), back pain (21.6%), and gastrointestinal symptoms, such as diarrhea (20.6%).

Olaparib is currently approved as a maintenance treatment, monotherapy, and/or combination therapy for numerous cancer types, including ovarian, breast, pancreatic, and prostate cancers.

In December 2022, the European Commission approved olaparib with abiraterone to treat mCRPC in adult men who are not clinically indicated to receive chemotherapy. The drug combination is now under regulatory review in other countries.

“Based on the totality of the data, it is notable to see this combination delivering a meaningful benefit in a broad population of patients in this setting, which is further underscored by the recent indication approved in the EU,” Galbraith said in the press release.

Reference

AstraZeneca. AstraZeneca and Merck present final results of key secondary overall survival endpoint from Phase III PROpel trial at ASCO GU Cancers Symposium. News Release. February 16, 2023. Acccessed on February 20, 2023. https://www.businesswire.com/news/home/20230216005538/en