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Homologous Recombination Repair Deficiency in Metastatic Prostate Cancer: New Therapeutic Opportunities

Piombino, Claudia, Pipitone, Stefania, Tonni, Elena, Mastrodomenico, Luciana, Oltrecolli, Marco, Tchawa, Cyrielle, Matranga, Rossana, Roccabruna, Sara +8 more·2024·International Journal of Molecular Sciences
DOI 10.3390/ijms25094624PMC PMC11083429
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Abstract

More than 20% of metastatic prostate cancer carries genomic defects involving DNA damage repair pathways, mainly in homologous recombination repair-related genes. The recent approval of olaparib has paved the way to precision medicine for the treatment of metastatic prostate cancer with PARP inhibitors in this subset of patients, especially in the case of BRCA1 or BRCA2 pathogenic/likely pathogenic variants. In face of this new therapeutic opportunity, many issues remain unsolved. This narrative review aims to describe the relationship between homologous recombination repair deficiency and prostate cancer, the techniques used to determine homologous recombination repair status in prostate cancer, the crosstalk between homologous recombination repair and the androgen receptor pathway, the current evidence on PARP inhibitors activity in metastatic prostate cancer also in homologous recombination repair-proficient tumors, as well as emerging mechanisms of resistance to PARP inhibitors. The possibility of combination therapies including a PARP inhibitor is an attractive option, and more robust data are awaited from ongoing phase II and phase III trials outlined in this manuscript.

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  • HRD is the most well-established predictive biomarker in advanced prostate cancer, with alterations in BRCA1, BRCA2, and ATM associated with sensitivity to PARP inhibitors.

    “HRD represents the most well-established predictive biomarker, with alterations in genes such as BRCA1, BRCA2, and ATM associated with sensitivity to PARP inhibitors [8,9].”

    From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [8]

    Section 4 reports the greatest PARP-inhibitor effectiveness in patients with BRCA1/2 alterations, supporting those genes as predictors of response. It says efficacy with alterations in other genes remains uncertain; for ATM, it reports a weaker response in one trial and no objective responses in another. The copy also does not establish HRD as the *most* well-established predictive biomarker. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Germline, somatic, and liquid biopsy-based approaches are increasingly indispensable in advanced disease, particularly when they identify actionable alterations such as HRD or dMMR.

    “In contrast, germline, somatic, and liquid biopsy–based approaches are increasingly indispensable in advanced disease, particularly when they identify actionable alterations such as homologous recombination repair deficiency or mismatch repair deficiency [8–10, 18].”

    From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [8]

    Section 3, “Identification of HRD in PC” (page not provided), describes germline, tumor-tissue, and liquid-biopsy tests for HRR alterations that can guide PARP-inhibitor treatment. It also says cfDNA’s role in determining HRR status in prostate cancer remains dubious, so “indispensable” overstates its position. The cited passages do not establish the claim about mismatch repair deficiency. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In advanced prostate cancer, germline and somatic testing identify predictive biomarkers linked to therapy selection.

    “in advanced disease, germline and somatic testing identify predictive biomarkers linked to therapy selection”

    From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [8]

  • Therapeutic benefit from PARP inhibitors is not uniform across HRD genes, with BRCA2 alterations typically conferring the strongest response.

    “However, therapeutic benefit is not uniform across genes, with BRCA2 alterations typically conferring the strongest response.”

    From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [8]

  • National data indicate that use of genomic assays such as Decipher has increased in the United States, but uptake remains uneven and may reflect payer, practice, and regional differences rather than purely evidence-driven diffusion.

    “National data indicate that use of genomic assays such as Decipher has increased in the United States, but uptake remains uneven and may reflect payer, practice, and regional differences rather than purely evidence-driven diffusion [8].”

    From A decision-oriented framework for genomic testing across the prostate cancer continuum (2026) · cites this paper as [8]

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Cited by

Sorted by citations

Authors
Piombino, C., Pipitone, S., Tonni, E., Mastrodomenico, L., Oltrecolli, M., Tchawa, C., Matranga, R., Roccabruna, S., D’Agostino, E., Pirola, M., Bacchelli, F., Baldessari, C., Baschieri, M. C., Dominici, M., Sabbatini, R., & Vitale, M. G.
Affiliations
  • Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, 41124 Modena, Italy
  • Clinical Trials Office, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy
  • Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2024-04-24
Volume
25
Issue
9
Pages
4624
ISSN
1422-0067
DOI
10.3390/ijms25094624
PMC
PMC11083429
Cited by
15
References
3
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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