Abstract CT031: TALAPRO-1: Talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with tumor DNA damage response alterations (DDRm)– Exploration of genomic loss of heterozygosity (gLOH) and potential associations with antitumor activity

医学 前列腺癌 肿瘤科 内科学 人口 紫杉烷 临床终点 激素疗法 癌症 PARP抑制剂 乳腺癌 临床试验 生物 生物化学 环境卫生 聚合酶 聚ADP核糖聚合酶 基因
作者
Johann S. de Bono,Niven Mehra,A. Douglas Laird,Elena Castro,Philippe Barthélémy,R. Delva,Giorgio V. Scagliotti,Marco Maruzzo,Adam Stirling,Jean‐Pascal Machiels,Herlinde Dumez,Vincent Renard,Julia F. Hopkins,Lee A. Albacker,Hsiang-Chun Chen,Cynthia G. Healy,Jijumon Chelliserry,Tanya B. Dorff,Karim Fizazi
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:82 (12_Supplement): CT031-CT031
标识
DOI:10.1158/1538-7445.am2022-ct031
摘要

Abstract Background: TALAPRO-1 enrolled men with progressive mCRPC, measurable soft-tissue disease, and tumor DDRm involved directly or indirectly in homologous recombination repair (HRR) (11 gene panel). Men had received 1-2 taxane-based chemotherapy regimens and progressed on ≥1 novel hormonal therapy. The primary endpoint was objective response rate ([ORR] per RECIST 1.1; blinded independent central review [BICR]). Exploratory ad hoc biomarker analyses assessed gLOH and associations with antitumor activity. Methods: gLOH was calculated as previously described (Sokol et al., JCO Precis Oncol 2020; PMID: 32903788). Of 104 men in the HRR-deficient measurable disease population (hereafter referred to as the efficacy population), 55 were evaluable for gLOH, 45 were non-evaluable for gLOH, and four lacked central lab gLOH results. Potential association of gLOH high/low status with response was explored using two high/low thresholds: 8.8% based on literature showing that this threshold optimally distinguished prostate cancers bearing BRCA biallelic alterations from BRCA-wildtype (Sokol et al., JCO Precis Oncol 2020; PMID: 32903788), and an agnostic threshold based on the median gLOH score in TALAPRO-1 (9.2%) in the gLOH-evaluable efficacy population. Data cutoff was Sept 4, 2020 (primary completion date). Results: gLOH ranged from 1.39% to 30.2% in the gLOH-evaluable efficacy population. Based on the 8.8% gLOH threshold, ORR was significantly higher for gLOH-high (53.3% [16/30], 95% confidence interval [CI] 34.3-71.7%) vs gLOH-low (12.0% [3/25], 95% CI 2.5-31.2%; odds ratio [OR] 8.381, 2-sided P=0.0017; Fisher’s exact test). Similar results were yielded based on the 9.2% gLOH threshold. Next, potential associations of gLOH score with response within HRR gene alteration groups of the efficacy population were explored using the 8.8% threshold. Within the BRCA2 group, ORR was robust regardless of gLOH status, but was significantly higher for gLOH-high (70.6%, 12/17) than for gLOH-low (23.1%, 3/13) (P=0.0253). Within the ATM group, ORR was numerically higher for gLOH-high (50.0%, 2/4) than gLOH-low (0%, 0/6), but not significantly (P=0.1333). Radiographic progression-free survival (RECIST 1.1; BICR) in the gLOH-evaluable efficacy population was numerically superior for gLOH-high versus gLOH-low using either threshold (hazard ratio 0.68), but not significantly. Conclusions: Based on these retrospective, exploratory analyses of TALAPRO-1, gLOH-high status was associated with response within the gLOH-evaluable efficacy population. Further exploration of gLOH as a candidate predictive biomarker for talazoparib in prostate cancer is warranted. Citation Format: Johann S. de Bono, Niven Mehra, A. Douglas Laird, Elena Castro, Philippe Barthelemy, Remy Delva, Giorgio V. Scagliotti, Marco Maruzzo, Adam Stirling, Jean-Pascal Machiels, Herlinde Dumez, Vincent Renard, Julia F. Hopkins, Lee A. Albacker, Hsiang-Chun Chen, Cynthia G. Healy, Jijumon Chelliserry, Tanya Dorff, Karim Fizazi. TALAPRO-1: Talazoparib monotherapy in metastatic castration-resistant prostate cancer (mCRPC) with tumor DNA damage response alterations (DDRm)– Exploration of genomic loss of heterozygosity (gLOH) and potential associations with antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT031.

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