Harnessing HRD Testing and MYC Amplification to Optimize PARP Inhibitor Use in BRCA Wild-Type High-Grade Serous Ovarian Carcinoma

Introduction

High-grade serous carcinoma (HGSC) of the tubo-ovarian region remains a significant clinical challenge due to its aggressive nature and frequent relapse. The advent of poly (ADP-ribose) polymerase inhibitors (PARPi) has transformed treatment strategies, leveraging defects in DNA repair pathways to induce synthetic lethality. A key biomarker predicting PARPi benefit is homologous recombination deficiency (HRD), a genomic instability hallmark primarily driven by BRCA1 or BRCA2 mutations. However, many HGSC cases are BRCA1/2 wild-type (BRCA-wt), limiting the predictive utility of BRCA status alone for PARPi responsiveness. The availability and routine adoption of HRD testing are also variable in clinical practice settings. Importantly, alternative molecular markers that reliably infer HRD status could enhance patient stratification for PARPi therapy.

Study Background

The study by Maradiya et al. addresses critical knowledge gaps regarding the real-world clinical utility of HRD testing in patients with BRCA-wt HGSC. Furthermore, it investigates MYC amplification, a common oncogenic event, as a candidate surrogate marker associated with HRD status and potential PARPi responsiveness. Such surrogate biomarkers could simplify molecular testing and broaden precision medicine applications in ovarian cancer.

Study Design and Methods

This retrospective cohort study evaluated 96 patients with HGSC who underwent HRD testing between January 2023 and 2025 at institutions in Alberta, Canada. Patients were stratified based on HRD status determined by established DNA-based assays as HRD, homologous recombination proficient (HRP), or inconclusive. The analysis focused on demographic data, treatment regimen details, especially PARPi use (predominantly niraparib), tumor genetic profiles, and recurrence outcomes. Two independent BRCA-wt cohorts were used to validate observations regarding the association between MYC copy number alterations and HRD status.

Key Findings

The cohort comprised 33 HRD, 59 HRP, and 4 inconclusive cases. Importantly, HRD tumors were 3.5 times more likely to receive niraparib (25/33) compared to HRP tumors (13/59), suggesting clinical application of HRD testing results in treatment decision-making. Among niraparib-treated patients, a higher proportion with HRD tumors (40%) continued treatment without progression compared to those with HRP tumors (23%), indicating a better therapeutic response consistent with underlying genomic vulnerabilities.

Crucially, MYC amplification (≥5 copies) emerged as significantly more prevalent in HRD versus HRP tumors in both the main cohort (43% vs 3%, p=0.00050) and validation cohorts (55% vs 11%, p<0.005). The presence of MYC amplification correlated with an estimated 85% probability of HRD—a 2.6-fold increase over the baseline 33% HRD prevalence across cohorts. This strong association underscores the potential of MYC amplification as a surrogate biomarker identifying patients likely to benefit from PARPi despite BRCA-wt status.

Expert Commentary

The study’s findings reinforce the clinically actionable role of HRD testing in guiding PARPi therapy, aligning with emerging guidelines that advocate biomarker-driven treatment selection in HGSC. MYC amplification as a surrogate marker is a novel and promising concept that warrants further biological and clinical validation. Its utility in routine clinical DNA panels could enable streamlined, cost-effective screening and improve the therapeutic index of PARPi in BRCA-wt patients.

Limitations include the retrospective design and potential selection biases inherent in real-world studies. The relatively small sample size for subgroup analyses calls for caution in interpreting statistical associations. Furthermore, standardization of HRD assays and cut-offs remains an ongoing challenge in the field. Prospective studies integrating comprehensive genomic profiling and longitudinal clinical outcomes will be essential to confirm and extend these observations.

Conclusion

Maradiya et al. provide compelling evidence that HRD testing is a valuable tool to inform PARPi use in HGSC, particularly for BRCA1/2 wild-type tumors. Their identification of MYC amplification as a highly predictive surrogate marker of HRD offers a novel biomarker strategy that could enhance patient selection for targeted therapies. Integration of MYC copy number assessment into clinical DNA panels holds promise for expanding precision oncology in ovarian cancer. Moving forward, harmonized testing approaches and prospective validation will be critical to translate these insights into improved patient outcomes.

Funding and Trial Registration

The original publication does not specify funding sources or clinical trial registration; further details should be sought from the authors and associated institutions.

References

1. Maradiya R, Kinloch M, De Leo A, et al. The real-world utility of homologous repair deficiency testing in BRCA1/2 wild-type high-grade serous carcinoma and the utility of MYC amplification as a potential surrogate marker. Gynecol Oncol. 2026 Jul 13;211:148-152. PMID: 42442041.

2. Ledermann J et al. Overall survival in patients with platinum-sensitive recurrent ovarian cancer treated with niraparib: an updated analysis of the ENGOT-OV16/NOVA trial. Ann Oncol. 2019.

3. Alexandrov LB et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415-21.