Talazoparib Monotherapy in Metastatic Castration-resistant Prostate Cancer with DNA Damage Response Alterations-Genomic Features Associated with Response to Therapy.
[BACKGROUND AND OBJECTIVE] The impact of alterations beyond DNA damage response-homologous recombination repair (DDR-HRR) genes on outcomes with poly(ADP-ribose) polymerase inhibitor monotherapy remai
- p-value p = 0.044
- p-value p = 0.0017
APA
Fizazi K, de Bono JS, et al. (2025). Talazoparib Monotherapy in Metastatic Castration-resistant Prostate Cancer with DNA Damage Response Alterations-Genomic Features Associated with Response to Therapy.. European urology oncology, 8(6), 1617-1628. https://doi.org/10.1016/j.euo.2025.09.016
MLA
Fizazi K, et al.. "Talazoparib Monotherapy in Metastatic Castration-resistant Prostate Cancer with DNA Damage Response Alterations-Genomic Features Associated with Response to Therapy.." European urology oncology, vol. 8, no. 6, 2025, pp. 1617-1628.
PMID
41173779
Abstract
[BACKGROUND AND OBJECTIVE] The impact of alterations beyond DNA damage response-homologous recombination repair (DDR-HRR) genes on outcomes with poly(ADP-ribose) polymerase inhibitor monotherapy remains unknown. This study aims to explore the impact of genomic features and co-occurring alterations on treatment outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) and DDR-HRR alterations in TALAPRO-1.
[METHODS] TALAPRO-1 evaluated talazoparib monotherapy in heavily pretreated patients with mCRPC and DDR-HRR alterations. We used tumor and saliva alteration results, and somatic-germline-zygosity prediction to assess genomic alterations.
[KEY FINDINGS AND LIMITATIONS] Associations between antitumor activity and gene alteration origin, selected non-DDR-HRR gene alteration status, tumor mutational burden, and genomic loss of heterozygosity (gLOH) were explored. Objective response rates (ORRs) and median overall survival (OS) with 95% confidence intervals (Clopper-Pearson method) and p values (two-sided Fisher's exact test) were calculated. Commonly altered non-DDR-HRR genes included TMPRSS2, TP53, PTEN, androgen receptor (AR), MYC, and SPOP. ORRs were 30.0% and 34.5% in men with TP53 and PTEN alterations, respectively, and 28.6% and 26.8% in men without TP53 or PTEN alterations, respectively. In tumors bearing ATM alterations, ORR was greater in those with (two of four) versus without PTEN alterations (zero of 13; p = 0.044). ORR was significantly higher for gLOH-high than for gLOH-low patients (53.3% vs 12.0%; p = 0.0017). The median OS for gLOH-high patients was 23.7 mo versus 18.7 mo for gLOH-low patients (hazard ratio 0.92, 95% confidence interval 0.52-1.64). Our analyses are retrospective and limited by small subgroup sizes.
[CONCLUSIONS AND CLINICAL IMPLICATIONS] In men with mCRPC, high gLOH status was associated with enhanced responses to talazoparib.
[METHODS] TALAPRO-1 evaluated talazoparib monotherapy in heavily pretreated patients with mCRPC and DDR-HRR alterations. We used tumor and saliva alteration results, and somatic-germline-zygosity prediction to assess genomic alterations.
[KEY FINDINGS AND LIMITATIONS] Associations between antitumor activity and gene alteration origin, selected non-DDR-HRR gene alteration status, tumor mutational burden, and genomic loss of heterozygosity (gLOH) were explored. Objective response rates (ORRs) and median overall survival (OS) with 95% confidence intervals (Clopper-Pearson method) and p values (two-sided Fisher's exact test) were calculated. Commonly altered non-DDR-HRR genes included TMPRSS2, TP53, PTEN, androgen receptor (AR), MYC, and SPOP. ORRs were 30.0% and 34.5% in men with TP53 and PTEN alterations, respectively, and 28.6% and 26.8% in men without TP53 or PTEN alterations, respectively. In tumors bearing ATM alterations, ORR was greater in those with (two of four) versus without PTEN alterations (zero of 13; p = 0.044). ORR was significantly higher for gLOH-high than for gLOH-low patients (53.3% vs 12.0%; p = 0.0017). The median OS for gLOH-high patients was 23.7 mo versus 18.7 mo for gLOH-low patients (hazard ratio 0.92, 95% confidence interval 0.52-1.64). Our analyses are retrospective and limited by small subgroup sizes.
[CONCLUSIONS AND CLINICAL IMPLICATIONS] In men with mCRPC, high gLOH status was associated with enhanced responses to talazoparib.
MeSH Terms
Humans; Male; Prostatic Neoplasms, Castration-Resistant; Phthalazines; Aged; Middle Aged; DNA Damage; Poly(ADP-ribose) Polymerase Inhibitors; Aged, 80 and over; Neoplasm Metastasis; Treatment Outcome
같은 제1저자의 인용 많은 논문 (5)
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- Nivolumab plus docetaxel versus placebo plus docetaxel for androgen receptor pathway inhibitor-pretreated and chemotherapy-naive metastatic castration-resistant prostate cancer (CheckMate 7DX): a double-blind, randomised, phase 3 trial.
- Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study.
- Talazoparib plus enzalutamide in men with HRR-deficient metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial.
- Health-related quality of life, pain, and symptomatic skeletal events with [Lu]Lu-PSMA-617 in patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): an open-label, randomised, phase 3 trial.