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SAN FRANCISCO -- Adding the PARP inhibitor olaparib (Lynparza) to standard-of-care abiraterone (Zytiga) as initial treatment for metastatic castration-resistant prostate cancer (mCRPC) extended median progression-free survival (PFS), according to final results of the double-blind reported here.

There was also a trend toward an improvement in median overall survival (OS). At the final prespecified analysis in the intent-to-treat (ITT) population, performed at 47.9% maturity for OS, median OS was 42.1 months in the abiraterone plus olaparib arm, as compared with 34.7 months in the abiraterone plus placebo arm (HR 0.81, 95% CI 0.67-1.00, P=0.0544), reported Noel Clarke, MBBS, of the Christie and Salford Royal NHS Foundation Trusts in Manchester, England.

The improvement in OS of more than 7 months with the addition of olaparib "represents one of the largest reported in a phase III trial in first-line mCRPC," Clarke said at the Genitourinary Cancers Symposium (GuCS). "The overall results, in conclusion, support combination treatment with abiraterone plus olaparib as an important new first-line treatment in patients with mCRPC."

Outcomes in mCRPC have remained poor despite first-line standard treatment with abiraterone, with a median OS of approximately 3 years in a clinical trial setting and less than 2 years in clinical practice. First-line selection of treatment is critical because half of patients with mCRPC receive only one line of treatment.

Both PARP and the androgen receptor (AR) are important for DNA repair in prostate cancer, Clarke explained. PARP activity facilitates repair of DNA single-strand breaks and AR binds DNA and facilitates repair through multiple pathways. Inhibition of both PARP and AR results in excess DNA damage compared with either alone, which increases the efficacy of anti-prostate cancer therapy.

In the primary analysis of PROpel, reported at last year's GuCS meeting, the olaparib arm demonstrated a significant 34% reduction in the risk of disease progression or death compared with the placebo arm (HR 0.66, 95% CI 0.54-0.81, P<0.0001).

In the current analysis, a total of 796 patients with histologically or cytologically confirmed prostate adenocarcinoma with at least one documented metastatic lesion on imaging were randomized 1:1 to abiraterone (1,000 mg once daily) in combination with either olaparib (300 mg twice daily) or placebo. All patients also received prednisone or prednisolone (5 mg twice daily). Patients were enrolled regardless of their homologous recombination repair gene mutation (HRRm) status.

Data cut-off for the final prespecified OS analysis was Oct, 12, 2022. Results across subgroups were consistent with those in the ITT population, Clarke reported. In the HRRm population, which represented 28.4% of the ITT population, median OS was not reached in the olaparib arm, compared with 28.5 months in the placebo arm (HR 0.66, 95% CI 0.45-0.95). In the non-HRRm arm, which represented 69.3% of the ITT population, median OS was 42.1 months in the olaparib arm compared with 38.9 months in the placebo arm (HR 0.89, 95% CI 0.70-1.14).

Interpreting the OS differences in the treatment arms by HRRm status is difficult, Clarke noted. "These are somewhat different populations. Patients in the control arm in the HRRm group have a much more aggressive phenotype than those in the non-HRRm group. Notwithstanding, there is improved survival."

In the subgroup of patients with BRCA mutations, median OS was not reached in the olaparib arm compared with 23.0 months in the placebo arm (HR 0.29, 95% CI 0.14-0.56). In those without BRCA mutations, median OS was 39.6 months and 38.0 months in the two arms, respectively (HR 0.91, 95% CI 0.73-1.13).

Time to first subsequent therapy, a key secondary endpoint, also favored the combination (HR 0.76, 95% CI 0.64-0.90), as did time to second disease progression (HR 0.76, 95% CI 0.59-0.99).

Some 44.9% in the combination arm and 54.2% in the abiraterone-placebo arm had a subsequent therapy, most commonly cytotoxic chemotherapy (n=242) or hormonal therapy (n=113). Three patients in the abiraterone-placebo arm received a PARP inhibitor as their first subsequent therapy.

The safety and tolerability of olaparib plus abiraterone remained consistent over time, with no new safety signals, Clarke said.

The most common adverse events in the olaparib arm (≥20% of patients) were anemia (49.7%), fatigue (38.7%), nausea (30.7%), back pain (21.6%), and diarrhea (20.6%). Two patients in this arm developed myelodysplastic syndromes/acute myeloid leukemia. The incidence of new primary malignancies and pneumonitis was balanced between the two arms.

No diminution in quality of life was observed with olaparib plus abiraterone at the final data cut-off, Clarke noted.

"It was no surprise that the benefit to the combination was most pronounced in the BRCA-mutated patients in this study, because we know that PARP inhibition works best in the BRCA-mutated population," commented Bradley McGregor, MD, of Dana-Farber Cancer Institute in Boston. Other studies, such as TALAPRO-2 and TRITON3, have demonstrated efficacy of single-agent PARP inhibition in mCRPC, particularly in the HRRm population, specifically those with BRCA mutations, he noted.

The findings provide "an opportunity for continued discussion" about optimal patient selection for the combination, especially since many patients will already have progressed on intensive androgen-deprivation therapy alone for hormone-sensitive prostate cancer prior to developing mCRPC, McGregor added.

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