Olaparib Combined with Abiraterone Significantly Reduces Risk of Disease Progression in First-Line mCRPC Treatment

February 14 News: Olaparib, the PARP inhibitor jointly developed by AstraZeneca and MSD (Merck & Co., Inc.), achieved positive results in the Phase 3 PROpel trial for first-line treatment of metastatic castration-resistant prostate cancer (mCRPC): compared with abiraterone alone, the combination of olaparib and abiraterone reduced the risk of disease progression by 34%. Moreover, regardless of whether there were homologous recombination repair (HRR) gene mutations, the combination therapy provided clinical benefits to patients. According to the press release, these results will be presented on February 17 at the 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium.

Public information shows that olaparib (brand name: Lynparza) is a PARP inhibitor. It targets the DNA Damage Response (DDR) pathway and utilizes the principle of "synthetic lethality" to kill cancer cells without affecting healthy cells. In China, olaparib was first approved in August 2018 and has since been approved for multiple indications in diseases such as ovarian cancer and prostate cancer.

PROpel Trial is a randomized, double-blind, multicenter Phase III trial designed to evaluate the efficacy, safety, and tolerability of olaparib in combination with abiraterone versus abiraterone monotherapy in men with mCRPC who have not received prior chemotherapy or novel hormonal agent (NHA) treatment in the first-line setting. The primary endpoint of the trial is radiographic progression-free survival (rPFS), with secondary endpoints including overall survival (OS), second progression-free survival (PFS2), and time to first subsequent treatment (TFST).

The trial results showed that, in the pre-defined interim analysis, compared with abiraterone alone, the combination of olaparib and abiraterone reduced the risk of disease progression or death by 34%, with a rPFS of 24.8 months in the combination group (vs 16.6 months). In addition, there was also a trend towards OS improvement with the combination therapy (the difference did not reach statistical significance at the data cutoff), and the trial will continue to evaluate OS as a key secondary endpoint. Other data from efficacy endpoints such as TFST, PFS2, objective response rate (ORR), prostate-specific antigen levels, and circulating tumor cell counts further support the therapeutic benefits of the combination regimen across the entire trial population.

▲PROpel Trial Partial Results (Screenshot Source: Reference [1])

In the trial, the safety and tolerability of olaparib in combination with abiraterone were consistent with the findings observed in previous clinical trials and the known profiles of the individual drugs. The most common adverse events (AEs) in the study were mainly anemia (45%), nausea (28%), and fatigue (28%), with grade 3 or higher AEs primarily being anemia (15%).

Professor Fred Saad, the chief investigator of the PROpel trial, stated that patients with mCRPC have a poor prognosis, and many patients can only receive one effective treatment. The results of the PROpel trial indicate that, compared to abiraterone alone, the combination of olaparib and abiraterone significantly delays disease progression by more than 8 months. This suggests that, if approved, this combination has the potential to become a new option for the standard of care in mCRPC.

Prostate cancer is one of the common cancers in male patients. mCRPC is a serious type of prostate cancer where the cancer has spread to other parts of the body, and even though the level of androgens in the body has been significantly reduced, the tumor continues to grow. Despite an increase in available treatments for men with mCRPC, the five-year survival rate remains very low. In mCRPC patients, approximately 20% to 30% will experience mutations in HRR genes. Previously, olaparib was approved in the United States for mCRPC patients with HRR gene mutations. The positive results from the PROpel trial indicate that this PARP inhibitor has the potential to benefit a broader patient population.

References:

[1]Lynparza plus abiraterone reduced risk of disease progression by 34% vs. standard-of-care in 1st-line metastatic castration-resistant prostate cancer. Retrieved Feb 14，2022, from https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2022/lynparza-combo-delays-progression-risk-in-prostate-cancer.html

(Original text has been abridged)

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