1. Fuerst, Mark L.

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Adding the PARP inhibitor olaparib to standard-of-care abiraterone shows a trend toward improvement in overall survival (OS) by more than 7 months in the first-line treatment of metastatic castrate-resistant prostate cancer (mCRPC), according to final OS results of the PROpel trial. These findings add to the significant radiographic progression-free survival (rPFS) benefit seen with olaparib plus abiraterone in PROpel's primary endpoint analysis presented last year (J Clin Oncol 2022; doi: 10.1200/JCO.2022.40.6_suppl.011).

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"The rPFS and OS benefit was observed across the subgroups, irrespective of homologous recombination repair (HRR) mutational status. The safety profile was consistent over time, with no new signals observed. The overall results support the combination treatment with abiraterone and olaparib as an important new first-line treatment in patients with mCRPC," said lead author Noel Clarke, MBBS, Professor of Urological Oncology for the Christie NHS Foundation Trust in Manchester, England, at the 2023 ASCO Genitourinary Cancers Symposium (Abstract LBA16).


The combination of olaparib with abiraterone and prednisone has been approved by the European Commission for adult patients with mCRPC where chemotherapy is not clinically indicated. The FDA is currently reviewing a supplementary new drug application for olaparib in combination with abiraterone and prednisone.


Patients with mCRPC have a poor outcome, with rPFS and OS poor despite the current standard of care. A significant proportion of patients (about half) do not receive second-line treatment once they fail first-line therapy for mCRPC, Clarke noted.


PARP activity facilitates the repair of DNA single-strand breaks through HRR, and androgen receptor also binds DNA and facilitates repair through multiple pathways. PARP enables androgen receptor binding to damage DNA and facilitates that DNA repair, he said.


"Olaparib stops that or limits that single-strand DNA repair by PARP trapping. In combination with androgen receptor inhibition, this increases the amount of DNA damage. So that effect is seen not only in HRR-mutated cells, but also in cells which are HRR wild-type," Clarke explained.


Study Details

In the international, Phase III PROpel trial, 796 patients with mCRPC were randomly assigned to olaparib 300 mg twice daily plus abiraterone 1,000 mg once daily and prednisone/prednisolone 5 mg twice daily or to abiraterone plus prednisone alone. All patients were assessed for HRR mutation status.


After the trial's initial data cutoff, median rPFS was almost 8 months longer with olaparib plus abiraterone (24.8 months) compared with abiraterone alone regardless of HRR mutation status (16.6 months) (HR: 0.66). OS data were immature at this time.


In the pre-specified OS data cutoff, Clarke now reported a trend toward OS benefit in the intention-to-treat population who were given olaparib plus abiraterone compared with abiraterone alone (HR: 0.81). Median OS was 42.1 months with olaparib compared with 34.7 months with no olaparib.


In the HRR mutated population (28.4% of the ITT population), median OS was not reached in the olaparib arm as compared with 28.5 months in the placebo arm (HR: 0.66). In the non-HRR mutated group (69.3% of the ITT population), median OS was 42.1 months in the olaparib arm as compared with 38.9 months in the placebo arm (HR: 0.89).


"Clearly, the HRR-mutated cases are more effectively treated, but there is still a big effect in non-HRR mutated or wild-type disease," Clarke said.


In a subgroup of patients with BRCA mutations, median OS was not reached in the olaparib arm compared with 23 months in the placebo arm (HR: 0.29). For patients without BRCA mutations, median OS was 39.6 months in the olaparib group and 38 months in the placebo group (HR: 0.91). PARP inhibition is known to work best in BRCA-mutated patients. The treatment was well-tolerated overall. The side effects profile included anemia (49.7%), fatigue (38.7%), and nausea (30.7%), but the majority of these side effects occurred early.


"There was an increase in the complication rates with abiraterone and olaparib with a number of dose interruptions, some dose reductions, and an increase in the number of discontinuations. But these were generally very well-managed," Clarke noted.


There were two cases of MDS/AML in the olaparib abiraterone arm. The overall quality of life was not diminished in patients on the combination versus those receiving abiraterone alone.


Mark L. Fuerst is a contributing writer.