A panel-based mutational signature of homologous recombination deficiency associates with response to PARP inhibition in metastatic castration-resistant prostate cancer Journal Article
| Authors: | Boiarsky, D.; Tewari, A. K.; Gulhan, D. C.; Bakouny, Z.; Ananda, G.; Savignano, H.; Lakshminarayanan, G.; McClure, H. M.; Silver, R.; Choueiri, T. K.; Taplin, M. E.; Park, P. J.; Berchuck, J. E. |
| Article Title: | A panel-based mutational signature of homologous recombination deficiency associates with response to PARP inhibition in metastatic castration-resistant prostate cancer |
| Abstract: | Background: The PARP inhibitor (PARPi) olaparib is approved for homologous recombination repair (HRR) gene-altered metastatic castration-resistant prostate cancer (mCRPC). However, there is significant heterogeneity in response to PARPi in patients with mCRPC. Better clinical biomarkers are needed to identify patients likely to benefit from PARPi. Methods: Patients with prostate adenocarcinoma and panel sequencing at Dana-Farber Cancer Institute were identified. Mutational signature analysis was performed using SigMA to characterize tumors as HRR deficient (HRD). The validity of SigMA to identify patients likely to benefit from olaparib was compared to the current FDA label (presence of a deleterious alteration in one of 14 HRR genes). Results: 546 patients were identified, of which 34% were HRD. Among patients with HRR gene alterations, only patients with BRCA2 two-copy loss (2CL) were more likely to be HRD compared to patients without HRR gene alterations (74% vs 31%; P = 9.1 × 10-7). 28 patients with mCRPC received olaparib, of which 13 were HRD and 9 had BRCA2 2CL. SigMA improved upon the current FDA label for predicting PSA50 (sensitivity: 100% vs 90%; specificity: 83% vs 44%; PPV: 77% vs 47%; NPV: 100% vs 89%) and rPFS > 6 months (sensitivity: both 92%; specificity: 93% vs 53%; PPV: 92% vs 63%; NPV: 93% vs 89%). On multivariate analysis, incorporating prognostic clinical factors and HR gene alterations, SigMA-predicted HRD independently associated with improved PSA-PFS (HR = 0.086, p = 0.00082) and rPFS (HR = 0.078, p = 0.0070). Conclusions: SigMA-predicted HRD may better identify patients likely to benefit from olaparib as compared to the current FDA label. Larger studies are needed for further validation. © 2024 Wiley Periodicals LLC. |
| Keywords: | controlled study; aged; aged, 80 and over; middle aged; overall survival; somatic mutation; genetics; mutation; monotherapy; follow up; sensitivity and specificity; adenocarcinoma; biological marker; homologous recombination; metastasis; pathology; mutational analysis; proportional hazards model; neoplasm metastasis; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; multivariate analysis; prostate adenocarcinoma; piperazines; drug therapy; piperazine derivative; predictive value; olaparib; castration resistant prostate cancer; phthalazine derivative; phthalazines; diagnostic test accuracy study; clinical outcome; parp inhibitor; recombinational dna repair; very elderly; recombination repair; metastatic castration-resistant prostate cancer; humans; human; male; article; whole genome sequencing; prostatic neoplasms, castration-resistant; metastatic castration resistant prostate cancer; poly(adp-ribose) polymerase inhibitors; homologous recombination deficiency; mutational signature |
| Journal Title: | Prostate |
| Volume: | 84 |
| Issue: | 16 |
| ISSN: | 0270-4137 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2024-12-01 |
| Start Page: | 1479 |
| End Page: | 1489 |
| Language: | English |
| DOI: | 10.1002/pros.24788 |
| PUBMED: | 39252459 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
