Biomarker analysis and updated results from the Phase III PROpel trial of abiraterone and olaparib vs. abi and placebo as first-line (1L) therapy for patients with mCRPC

Prostate cancer is the second most frequently diagnosed cancer in men. There are no initial or early symptoms in most of the cases. Still, late symptoms may include fatigue due to anemia, bone pain, paralysis from spinal metastases, and renal failure from bilateral ureteral obstruction. According to the Cancer Treatment Centers of America (CTCA), more than 99% of prostate cancers are adenocarcinomas, which develop in the gland cells. It is common in men 50–64 years and over age 65; however, it can occur in men younger than 50 years. As per Delveinsight’s estimates, there are approximately 143,000 treatment-eligible Castration-Resistant Prostate Cancer (CRPC) patients in the United States in 2022, this includes both metastatic (mCRPC) and non-metastatic (nmCRPC) patients. 

The current standard treatment for patients with Castration-Resistant Prostate Cancer (CRPC) includes Androgen Deprivation therapies (ADTs), chemotherapy, Zytiga (abiraterone acetate), Xtandi (enzalutamide), PARP inhibitors including Lynparza (olaparib), and Rubraca (rucaparib), along with Xofigo (radium-223) (for bone metastases). Two PARP inhibitors, rucaparib, and olaparib received FDA approval in May 2020 for use in mCRPC harboring selected HRR aberrations after progression on at least one NAA therapy (olaparib) and at least one NAA and one chemotherapy (rucaparib). At present, the use of these agents is contingent upon the presence of aberrations in the HRR gene as identified on a commercial assay. Moreover, talazoparib (Talzenna, Pfizer) and niraparib (Zejula, Janssen) are also being investigated in combination with an AR-directed therapy for first-line treatment of mCRPC, similar to olaparib and rucaparib.

In the current CRPC market, Lynparza (olaparib) is the first and best-in-class oral poly ADP-PARP inhibitor, and the first targeted treatment to block DDR in tumors harboring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. Currently, there is a critical unmet need among patients diagnosed with mCRPC, where the prognosis remains poor, and treatment options are limited. There is a much-needed treatment option in the first-line mCRPC setting, where olaparib plus abiraterone is also being evaluated. The focus of this year’s prostate cancer abstracts is on PARP inhibitor, Lynparza, which was already approved in the year 2020 for second-line treatment for HRR gene mutated mCRPC, whereas, it is now heading towards the first-line setting irrespective of the HRR gene mutation in mCRPC patients. As per company reports in the full year 2021, Lynparza has already grabbed more than USD 1 billion in revenue in the United States, due to an increase in usage in ovarian, breast, and second-line prostate cancer patients. 

Recently in August 2022, the FDA accepted the Submission of Supplemental New Drug Application for LYNPARZA (olaparib) in Combination with Abiraterone and Prednisone or Prednisolone for Patients with mCRPC and Granted Priority Review. The FDA has also set a Prescription Drug User Fee Act (PDUFA), or target action, date in the fourth quarter of 2022.

With the data cutoff date of March 14, 2022, olaparib plus abiraterone produced a radiologic progression-free survival (rPFS) benefit that was 8.6 months longer than that achieved with abiraterone alone. The median rPFS in the investigative arm was 25.0 months vs. 16.4 months in the control arm. Moreover, the time to first subsequent therapy or death (TFST) and time to second progression or death (PFS2) data also supported a trend toward longer-term benefits with the olaparib regimen. Specifically, the TFST with olaparib plus abiraterone was 25.4 months vs. 19.5 months with abiraterone alone, and the PFS2 had not yet been reached in either arm.

As per the investigator, rPFS served as the primary endpoint of the trial, and OS served as a key secondary end point. Additional endpoints comprised TFST, PFS2, objective response rate, homologous recombination repair (HRR) gene mutation status by tissue, and circulating tumor DNA (ctDNA) testing, as well as safety and tolerability. During the primary analysis presented at ASCO-GU 2022 conference, a benefit was noted with the olaparib regimen across the HRR-mutated and non–HRR-mutated subgroups. Specifically, among those with HRR-mutated disease who received olaparib plus abiraterone, the median rPFS was not yet reached per investigator assessment vs. 13.9 months in those who were given abiraterone alone. In the non–HRR-mutated subgroup, those who received the investigative regimen had a median rPFS of 24.1 months vs. 19.0 months in those who were given the control regimen. In terms of safety and tolerability, the results were consistent with the primary analysis and the known profiles for abiraterone and olaparib. With the critical unmet need, if approved, LYNPARZA with abiraterone will become the first combination of a PARP inhibitor and a new hormonal agent for patients with mCRPC in a first-line setting.

Expert Opinion: “In the assessed biomarker subgroup analyses, there was an improvement of at least 5 months [with olaparib plus abiraterone vs. abiraterone alone], which was most pronounced in the BRCA-mutated subgroup”

“Updated results [from the] second interim analysis were consistent with the results from [the first analysis] and showed a continuing trend toward an OS benefit in the ITT population. The safety and tolerability results were generally consistent with the primary analysis and the known profiles for abiraterone and olaparib”

Get more detailed insights, at: Metastatic castration-resistant prostate cancer (mCRPC) Market, Metastatic Prostate Cancer Market, Ovarian Cancer Market, Pancreatic Cancer Market, ER positive HER2 negative Breast Cancer Market