INTRODUCTION AND OBJECTIVE:
Tumors with mutations associated with homologous recombination deficiency (HRD) are uncommon in prostate cancer (PCa) and variably responsive to PARP inhibition. To better identify tumors with HRD, we developed and validated a transcriptomic signature for HRD in PCa (HRD-P).
By using an established mutational signature for tumor HRD, we created and validated a 16-gene signature for HRD-P in six independent PCa cohorts (primary PCa, n=8,224; metastatic castrate-resistant PCa [mCRPC], n=328). Molecular and clinical features were compared between HRD-P+ tumors and those with single HR-gene mutations that would have qualified patients for recent PARP inhibitor trials for mCRPC.
HRD-P+ tumors were more numerous than tumors with single HR-gene mutations in primary (201/491, 41% vs 32/491 6.5%; Figure 1) and mCRPC (126/328, 38% vs 82/328, 25%) cases and HRD-P+ was more predictive of genomic instability suggestive of HRD. HRD-P+ was associated with shorter time to recurrence following surgery and shorter overall survival in men with mCRPC (Figure 2). In a prospective trial of mCRPC treated with olaparib (n=10), all three men with HRD-P+ experienced prolonged (>330 days) PSA progression-free survival.
These results suggest transcriptomics can identify more patients that harbor phenotypic HRD than single HR-gene mutations and support further exploration of transcriptionally defined HRD tumors perhaps in conjunction with genomic markers for therapeutic application.
Source of Funding:
This work was supported in part by the National Institutes of Health grant 5U01CA196390 (EMS), the Prostate Cancer Foundation (EMS), Department of Defense grant W81XWH-15-1-0661 (EMS and TLL), the 2019 Urology Care Foundation Residency Research Award Program and the Russell Scott, Jr., MD Urology Research Fund (ABW), as well as the University of Michigan Prostate Specialized Program of Research Excellence (SPORE) P50 CA186786-05 and the Early Detection Research Network grant UO1 CA111275 (AMC).