Discovery of a novel non-negative matrix factorization (NMF)-based homologous recombination deficiency (HRD) score and subsequent exploration in TALAPRO-2 (TP-2), a phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Fizazi Karim , Roh Whijae , Azad Arun , Mu Xinmeng Jasmine , Matsubara Nobuaki , Yip Steven , Zschaebitz Stefanie , Piulats Josep M. , Liu Glenn , Jones Robert J. , Saul Michelle , Engelsberg Arne , Chelliserry Jijumon , Laird Douglas , Agarwal Neeraj 
Published: June 2024

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Background: TP-2 (NCT03395197) demonstrated significantly improved radiographic progression-free survival (rPFS) in pts with mCRPC who received TALA + ENZA (n=402) vs PBO + ENZA (n=403). We discovered a novel NMF-based HRD score and used it to explore potential associations of HRD with efficacy in TP-2. Methods: The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset was used to train a novel NMF-based HRD predictive score incorporating gene expression (RNA seq) and homologous recombination repair (HRR)12 genomic features (mutations possibly or probably damaging by PolyPhen, deleterious by SIFT, or shallow/deep deletion; HRR12 genes: BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12). A previously published composite HRD score incorporating genomic loss of heterozygosity, large scale transitions, and telomeric allelic imbalances (Knijnenburg et al. Cell Rep. 2018;23:239-254.e6) was used as the “original” HRD reference score. HRR12 genomic features in TCGA-PRAD were associated with higher original and predicted HRD scores. Two datasets were used to generate the HRD score for TP-2: a FoundationOneLiquid CDx (F1LCDx) dataset (Azad et al. ASCO 2023, #5056) of prospectively collected/retrospectively analyzed plasma samples (n=681) and a tumor transcriptomic dataset generated via HTG’s Oncology Biomarker Panel (with 10 additional genes implicated in PARPi sensitivity; n=304). This NMF-based HRD score was then applied to the evaluable TP-2 safety population (n=285). Predicted HRD scores for TP-2 were categorized as high (≥0.46 [median]) or low (<median). Results: Although predicted HRD score is primarily based on gene expression, it proved significantly associated with HRR12 gene alteration (HRR12m) status based on F1LCDx variant calling of retrospectively sequenced ctDNA (Wilcoxon test P=3.3e-10). Of 89 pts with HRR12m by F1LCDx, 74% were HRD-high and 26% were HRD-low. Conversely, of 196 pts who were non-HRR12m by F1LCDx, 39% were HRD-high and 61% were HRD-low, suggesting the presence of a subgroup of pts who had HRD in the absence of detected HRR12m. In all-comers, TALA + ENZA demonstrated more favorable rPFS than PBO + ENZA in both HRD-high (hazard ratio [HR]=0.49, P=0.0036) and HRD-low (HR=0.48 , P=0.0062) pts. A similar trend was evident in the subgroup of pts lacking HRR12m. Conclusions: Our exploratory analysis of TCGA-PRAD resulted in discovery of a novel HRD score, incorporating both gene expression and HRR12 genomic attributes. In TP-2, this score was associated with ctDNA HRR12m status. HRD-high and HRD-low pts exhibited comparable rPFS benefit in terms of HR favoring TALA + ENZA over PBO + ENZA. Clinical trial information: NCT03395197 .