Introduction

The past five years have witnessed significant advancements in understanding and targeting homologous recombination deficiency (HRD) in cancer. This mini-review synthesizes recent research focusing on clinical applications of PARP inhibitors, mechanisms of resistance, and the exploration of alternative therapeutic targets in HRD cancers. The review is based solely on the provided list of publications.

Clinical Efficacy and Expansion of PARP Inhibitor Use

A major focus has been on evaluating the clinical efficacy of PARP inhibitors across various cancer types with HRD, particularly those harboring BRCA1 and BRCA2 mutations. Charles E. Geyer's group has investigated the role of adjuvant olaparib in patients with BRCA1/2-mutated breast cancer, demonstrating its benefit in improving outcomes (Andrew Tutt et al., 2020, New England Journal of Medicine; Andrew Tutt et al., 2021, New England Journal of Medicine). Furthermore, Jennifer K. Litton's work on the EMBRACA trial showed the final overall survival results of talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer (Jennifer K. Litton et al., 2020, Annals of Oncology).

In ovarian cancer, Kathleen N. Moore's group presented the 7-year follow-up data from the SOLO1 trial, demonstrating the long-term overall survival benefit of maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (Paul DiSilvestro et al., 2021, Journal of Clinical Oncology; Paul DiSilvestro et al., 2022, Journal of Clinical Oncology). Rebecca Kristeleit's research on the ATHENA-MONO trial evaluated rucaparib monotherapy as maintenance treatment in newly diagnosed ovarian cancer patients (Bradley J. Monk et al., 2020, Journal of Clinical Oncology; Bradley J. Monk et al., 2021, Journal of Clinical Oncology; Bradley J. Monk et al., 2022, Journal of Clinical Oncology). Xiaohua Wu's group investigated individualized starting doses of niraparib in platinum-sensitive recurrent ovarian cancer (NORA trial) (Xiaohua Wu et al., 2021, Annals of Oncology) and senaparib as first-line maintenance therapy in advanced ovarian cancer (Xiaohua Wu et al., 2024, Nature Medicine). I. Ray-Coquard's group presented final overall survival results from the PAOLA-1/ENGOT-ov25 trial evaluating olaparib plus bevacizumab as first-line maintenance in ovarian cancer (I. Ray-Coquard et al., 2022, Annals of Oncology; I. Ray-Coquard et al., 2023, Annals of Oncology).

The application of PARP inhibitors has also expanded to prostate cancer. Johann S. de Bono's group reported survival benefits with olaparib in metastatic castration-resistant prostate cancer (mCRPC) (Maha Hussain et al., 2020, New England Journal of Medicine). Karim Fizazi's group compared rucaparib to physician's choice in metastatic prostate cancer (Karim Fizazi et al., 2021, New England Journal of Medicine; Karim Fizazi et al., 2022, New England Journal of Medicine; Karim Fizazi et al., 2023, New England Journal of Medicine). Shahneen Sandhu's research focused on the MAGNITUDE study, evaluating niraparib with abiraterone acetate and prednisone as first-line therapy in mCRPC with and without HRR gene alterations (Kim N. et al., 2022, Journal of Clinical Oncology). K.N. Chi's group presented a second interim analysis of the MAGNITUDE trial (K.N. Chi et al., 2023, Annals of Oncology). Maha Hussain's group investigated abiraterone, olaparib, or their combination in mCRPC patients bearing HRR mutations in the BRCAAway trial (Maha Hussain et al., 2024, Journal of Clinical Oncology).

Susan M. Domchek's group conducted a phase II study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic variant in BRCA1, BRCA2, or PALB2 (Kim A. Reiss et al., 2021, Journal of Clinical Oncology).

Mechanisms of PARP Inhibitor Resistance and Alternative Therapeutic Targets

Understanding the mechanisms of PARP inhibitor resistance has become a critical area of investigation. Jing Wang's group reviewed the underlying mechanisms and clinical implications of PARP inhibitor resistance (He Li et al., 2020, Molecular Cancer). Christopher J. Lord's group identified Polθ inhibitors as a potential strategy to target PARP inhibitor resistance in BRCA-deficient cells (Diana Zatreanu et al., 2020, Nature Communications; Diana Zatreanu et al., 2021, Nature Communications). Further research by Vincenzo Costanzo's group showed that Polθ prevents fork breakage in the absence of BRCA2/RAD51 (Anjali Mann et al., 2022, Molecular Cell), while Simon J. Boulton's group demonstrated that POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells (Ondrej Beláň et al., 2022, Molecular Cell). Raphaël Ceccaldi's group found that Polθ is phosphorylated by PLK1 to repair double-strand breaks in mitosis (Camille Gelot et al., 2023, Nature). Elizabeth Harvey-Jones's group identified co-occurring BRCA1/2 reversions and mutations in TP53BP1, RIF1, and PAXIP1 in PARP inhibitor-resistant advanced breast cancer (Elizabeth Harvey-Jones et al., 2024, Annals of Oncology). Haico van Attikum's group showed that EXO1 protects BRCA1-deficient cells against toxic DNA lesions (Bert van de Kooij et al., 2024, Molecular Cell). Sharon B. Cantor's group discovered that FANCJ promotes PARP1 activity during DNA replication, which is essential in BRCA1 deficient cells (Ke Cong et al., 2024, Nature Communications).

BRCA1/2 Variants and Cancer Risk

Several studies focused on the prevalence and implications of BRCA1 and BRCA2 variants. Antonis C. Antoniou's group investigated cancer risks associated with BRCA1 and BRCA2 pathogenic variants (Shuai Li et al., 2020, Journal of Clinical Oncology; Shuai Li et al., 2021, Journal of Clinical Oncology; Shuai Li et al., 2022, Journal of Clinical Oncology). Yukihide Momozawa's group expanded the cancer risk profile for BRCA1 and BRCA2 pathogenic variants (Yukihide Momozawa et al., 2021, JAMA Oncology; Yukihide Momozawa et al., 2022, JAMA Oncology). Nasim Mavaddat's group characterized the pathology of tumors associated with pathogenic germline variants in breast cancer susceptibility genes (Nasim Mavaddat et al., 2021, JAMA Oncology; Nasim Mavaddat et al., 2022, JAMA Oncology). Fergus J. Couch's group investigated contralateral breast cancer risk among carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 (Siddhartha Yadav et al., 2022, Journal of Clinical Oncology; Siddhartha Yadav et al., 2023, Journal of Clinical Oncology). Steven A. Narod's group studied the impact of MRI surveillance on breast cancer mortality in women with BRCA1 and BRCA2 sequence variations (Jan Lubiński et al., 2024, JAMA Oncology).

Conclusion

The research from the past five years underscores the increasing importance of HRD as a therapeutic target in cancer. While PARP inhibitors have shown significant clinical benefit, understanding and overcoming resistance mechanisms remains a crucial challenge. Future research should focus on developing novel therapeutic strategies that target alternative DNA repair pathways and on refining patient selection criteria to maximize the efficacy of PARP inhibitors and other HRD-targeted therapies.

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