PARP inhibitor therapy changes paradigm of mCRPC management

Olaparib, a poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, represents a paradigm shift in management of metastatic castration-resistant prostate cancer (mCRPC) in view of the promising results shown in recent trials, said Professor Przemyslaw Twardowski of John Wayne Cancer Institute of Santa Monica, California, US, who spoke at the Uro-Oncology Asia 2020 conference.

Olaparib demonstrated tumour response in patients with germline BRCA mutated advanced prostate cancer in Study 42, as well as significant improvements in objective response rate (ORR), radiologic progression-free survival (rPFS) and overall survival (OS) in biomarker-positive patients (n=16) compared with biomarker-negative patients (n=33) (ORR, 87.5 percent vs 6.1 percent, p<0.001; rPFS, 9.8 months vs 2.7 months; p<0.001) (mOS, 13.8 months vs 7.5 months; p=0.05) in the TOPARP-A trial. The positive findings of olaparib in biomarker-selected mCRPC were confirmed in the TOPARP-B trial. [N Engl J Med 2015;373:1697-1708; Mateo J, et al, ASCO 2019, abstract 5005]

“PROfound is the first positive biomarker-selected phase III study evaluating a PARP inhibitor in patients with mCRPC. Results highlight the importance of genomic testing in this population,” said Twardowski.

The benefits of olaparib demonstrated in the PROfound study has led to a priority review granted by the US FDA in January 2020 for its use in patients with homologous recombination repair (HRR)-mutated mCRPC.

In the PROfound trial, mCRPC patients (median age, ≥67 years) with disease progression on prior new hormonal agent (eg, abiraterone acetate and/or enzalutamide) treatment who had HRR mutation in one of 15 genes (BRCA1/2 or ATM genes [cohort A, n=245] or other HRR mutations [cohort B, n=142]) confirmed by prospective tissue analysis were randomized (2:1) to receive olaparib tablets (300 mg BID) or physician’s choice of either enzalutamide (160 mg orally QD) or abiraterone acetate (1,000 mg orally QD, plus 5 mg prednisolone BID). [de Bono JS, et al, ASCO 2017, abstract TPS5091]

A significant improvement in rPFS was demonstrated with olaparib in cohort A (median, 7.39 months vs 3.55 months; hazard ratio [HR], 0.34; 95 percent confidence interval [Cl], 0.25 to 0.47; p<0.0001) compared with physician’s choice of enzalutamide or abiraterone. Consistent rPFS benefits of olaparib were shown across all predefined subgroups in cohort A. [Hussain M, et al, ESMO 2019, abstract LBA12_PR]

Similarly, rPFS was improved with olaparib (mPFS, 5.82 months vs 3.52 months; HR, 0.49; 95 percent CI, 0.38 to 0.63) vs physician’s choice of enzalutamide or abiraterone the overall population of patients with any of the qualifying HRR mutations.

Olaparib also demonstrated, in cohort A, a 21-fold increase in ORR (33.3 percent vs 2.3 percent; odds ratio, 20.86; 95 percent CI, 4.18 to 379.18; p<0.0001) as well as a statistically significant and clinically meaningful delay in time to pain progression (TTPP) assessed by Brief Inventory-Short Form (median TTPP, not reached vs 9.92 months; HR, 0.44; 95 percent CI, 0.22 to 0.91; p=0.0192) compared with physician’s choice of enzalutamide or abiraterone.

The adverse event (AE) profile of olaparib in PROfound was consistent with its known safety profile, with anaemia and nausea being the most common AEs.

“Clinical activity of olaparib was also shown in patients with alternations in non-BRCA HRR genes. These also predict responsiveness to immunotherapy,” said Twardoswki. “However, gene-level analysis is complex and exploratory, and detailed analysis of gene-level effects on multiple endpoints is ongoing.”