Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Aug:8:e2400014.
doi: 10.1200/PO.24.00014.

DNA-Damaging Therapies in Patients With Prostate Cancer and Pathogenic Alterations in Homologous Recombination Repair Genes

Laura S Graham  1 , Nicholas C Henderson  2 , Olesia Kellezi  2 , Clara Hwang  3 , Pedro C Barata  4 , Mehmet A Bilen  5 , Deepak Kilari  6 , Michael Pierro  6 , Bicky Thapa  6 , Abhishek Tripathi  7 , George Mo  8 , Matthew Labriola  9 , Joseph J Park  9 , Shoshana Rothstein  10 , Rohan Garje  11 , Vadim S Koshkin  12 , Vaibhav G Patel  13 , Tanya Dorff  14 , Andrew J Armstrong  9 , Rana R McKay  15 , Ajjai Alva  2 , Michael T Schweizer  8
Affiliations

DNA-Damaging Therapies in Patients With Prostate Cancer and Pathogenic Alterations in Homologous Recombination Repair Genes

Laura S Graham et al. JCO Precis Oncol. 2024 Aug.

Abstract

Purpose: Outcomes data for DNA-damaging therapeutics for men with prostate cancer (PC) and non-BRCA1/2 homologous recombination repair (HRR) mutations are limited. We evaluated outcomes by HRR alteration in men with PC treated with poly(ADP-ribose)polymerase inhibitors (PARPi) and/or platinum chemotherapy.

Methods: Retrospective data from the PROMISE consortium were used. Clinical outcomes differences were assessed between patients with BRCA1/2 mutations (cohort A) and those with HRR mutations without direct BRCA complex interaction (cohort B: ATM, CDK12, CHEK1, CHEK2, and FANCL). Outcomes in patients with HRR mutations with direct BRCA complex interaction were also explored (cohort C: RAD51B/C/D, RAD54L2, BARD1, GEN1, PALB2, FANCA, and BRIP1).

Results: One hundred and forty-six patients received PARPi (cohort A: 94, cohort B: 45, cohort C: 7) and 104 received platinum chemotherapy (cohort A: 48, cohort B: 44, cohort C: 10). PSA50 response rate to PARPi was higher in cohort A (61%) than cohort B (5%), P < .001. Median clinical/radiographic progression-free survival (crPFS) with PARPi in cohort A was significantly longer than in cohort B: 15.9 versus 8.7 months, P = .005. PSA50 response rate to platinum therapy was higher in cohort A (62%) than in cohort B (32%), P = .024, although crPFS was not significantly different. PSA50 response rate to PARPi and platinum was 40% and 32%, respectively, in cohort C. In multivariable analysis, cohort A had significantly improved overall survival and crPFS compared with cohort B with PARPi but not platinum chemotherapy.

Conclusion: Patients with BRCA1/2-mutated PC had significantly improved outcomes to PARPi but not platinum chemotherapy compared with those with HRR mutations without direct BRCA complex interaction.

PubMed Disclaimer

Conflict of interest statement

CH: Stock holdings in Johnson and Johnson; research funding to institution from Merck, Bausch Health, Genentech, Bayer, and AstraZeneca, consultant fees from Tempus, Genzyme, and EMD Sorono, speaking fees from OncLive/MJH Life Sciences, travel fees from Merck, all outside the submitted work. PB: Consultant (Institutional): Astellas; Eisai; Janssen, EMD Serono; Dendreon; Pfizer, Seattle Genetics, BMS, Bayer, Exelixis, AVEO Oncology, Guardant Health; Contracted Research (Institutional): AstraZeneca, Merck, AVEO Oncolgy; Research Grant (Institutional): BlueEarth Diagnostics, Exelixis; Speaker’s Bureau (Institutional): Bayer, Caris, Myovant. MB: paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi and has received grants to his institution from Merck, Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, and Pfizer for work performed as outside of the current study. DK: D Kilari has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Eisai, Pfizer, Merck, Myovant and Sanofi and has received grants to his institution from Astellas, Genentech/Roche and Exelixis for work performed as outside of the current study. Speaker’s Bureau: Janssen. Seagen and Aveo oncology. VK: served in a consulting or advisory role for AstraZeneca, Clovis, Janssen, Pfizer, EMD Serono, Seagen, Astellas, Dendreon, Guidepoint, GLG and ExpertConnect; has received research funding for the institution from Endocyte, Nektar, Clovis, Janssen, Seagen and Taiho and is supported by the Prostate Cancer Foundation. VP: full-time employee at Arvinas and receives consulting fees from Seagen and Sanofi Genzyme. TD: Consulting: Bayer, Sanofi, Jamsen, Astellas. AA: Paid consultant or advisor for Bayer, Myovant, Pfizer, Janssen, Bayer, Dendreon, Novartis, BMS, Merck, Astrazeneca, Forma, Astellas, Exelixis. Research support to Duke from Bayer, Pfizer, Janssen, Bayer, Dendreon, Novartis, BMS, Merck, Astrazeneca, Forma, Astellas, Amgen. RM: Institutional research funding from Bayer, Tempus, AstraZeneca. Advisory Board/Consultant for Aveo, AstraZeneca, Bayer, Bristol Myers Squib, Calithera, Caris, Dendreon, Exelixis, Eli Lilly, Janssen, Merck, Myovant, Novartis, Pfizer, Sanofi, Seagen, Sorrento Therapeutics, Tempus, Telix. MTS: Paid consultant and/or received Honoria from Pfizer, Sanofi, AstraZeneca and Janssen. He has received research funding to his institution from Novartis, Zenith Epigenetics, Bristol Myers Squibb, Merck, Immunomedics, Janssen, AstraZeneca, Pfizer, Hoffman-La Roche, Tmunity, SignalOne Bio, Epigenetix, Xencor, Incyte and Ambrx, Inc. Other authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Clinical Outcomes for Patients Treated with PARPi.
(A) Clinical/radiographic Progression Free Survival. (B) Overall Survival.
Figure 1.
Figure 1.. Clinical Outcomes for Patients Treated with PARPi.
(A) Clinical/radiographic Progression Free Survival. (B) Overall Survival.
Figure 2.
Figure 2.. Clinical Outcomes for Patients Treated with Platinum Chemotherapy.
(A) Clinical/radiographic Progression Free Survival. (B) Overall Survival.
Figure 2.
Figure 2.. Clinical Outcomes for Patients Treated with Platinum Chemotherapy.
(A) Clinical/radiographic Progression Free Survival. (B) Overall Survival.
See this image and copyright information in PMC

References

    1. Annala M, Taavitsainen S, Khalaf DJ, et al. : Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition. Clin Cancer Res 27:4610–4623, 2021 - PubMed
    1. Khalaf DJ, Annala M, Taavitsainen S, et al. : Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol 20:1730–1739, 2019 - PubMed
    1. de Wit R, de Bono J, Sternberg CN, et al. : Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med 381:2506–2518, 2019 - PubMed
    1. Abida W, Armenia J, Gopalan A, et al. : Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making. JCO Precis Oncol 2017, 2017 - PMC - PubMed
    1. Pritchard CC, Mateo J, Walsh MF, et al. : Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375:443–53, 2016 - PMC - PubMed

Substances