What clinical trials are available for a patient with High-Grade Serous Carcinoma (HGSC) who is BRCA (Breast Cancer Gene) wild-type and Homologous Recombination Deficiency (HRD) negative?

Clinical Trials for HGSC BRCA Wild-Type, HRD-Negative Patients

For patients with high-grade serous carcinoma who are BRCA wild-type and HRD-negative, standard platinum-based chemotherapy remains the backbone treatment, with bevacizumab as an acceptable addition, though PARP inhibitor maintenance therapy shows limited benefit in this specific population. 1

Current Treatment Landscape for HRD-Negative HGSC

Standard First-Line Therapy

• Carboplatin (AUC 5-6) plus paclitaxel (175 mg/m²) every 3 weeks for six cycles remains the reference standard for first-line chemotherapy in advanced ovarian cancer, regardless of biomarker status. 1
• Bevacizumab 15 mg/kg can be added to chemotherapy and continued as maintenance for 15 months, which has demonstrated PFS benefit particularly in high-risk populations (stage III with macroscopic residual disease or stage IV). 1
• Weekly paclitaxel (60-80 mg/m²) with 3-weekly carboplatin represents an alternative regimen in select populations. 1

Maintenance Therapy Considerations for HRD-Negative Disease

• The role of maintenance therapy for patients with homologous recombination-proficient (HRP) tumors is not completely defined. 1
• PARP inhibitors show substantially less benefit in BRCA wild-type/HRD-negative patients compared to HRD-positive populations, with hazard ratios approaching 0.68-0.92 versus 0.4-0.5 in HRD-positive disease. 1
• In the PRIMA trial, niraparib showed benefit even in HRP tumors (HR 0.68; 95% CI 0.49-0.94), though this was less pronounced than in HRD-positive populations. 1
• Bevacizumab maintenance or observation may be considered for HRD-negative patients depending on trial design and clinical context. 1

Clinical Trial Opportunities

Biomarker-Agnostic Approaches

• Niraparib has been approved regardless of biomarker status based on the PRIMA trial, making it a potential option even for HRD-negative patients. 1
• Clinical trials evaluating novel combinations beyond PARP inhibitors are particularly relevant for this population, as they derive less benefit from standard PARP inhibitor monotherapy. 1

Alternative Therapeutic Strategies

• For HRD-negative/HRP tumors, clinical trials exploring non-PARP inhibitor maintenance strategies, including novel targeted agents or immunotherapy combinations, represent important opportunities. 1
• Bevacizumab-based maintenance remains a validated option with demonstrated PFS benefit in this population. 1
• Trials investigating mechanisms to overcome platinum resistance or enhance chemotherapy sensitivity are particularly relevant for HRD-negative disease. 2

Key Limitations of Current HRD Testing

Predictive Value Concerns

• Existing HRD tests lack adequate negative predictive value and fail to consistently identify a subgroup of patients who derive no benefit from PARP inhibitors. 1
• Current HRD assays do not provide sufficient differentiation of patient response to PARP inhibitors beyond BRCA-mutated tumors to routinely recommend their use for treatment exclusion. 1
• The complex and dynamic nature of the HRD phenotype is inadequately addressed by current testing methodologies. 1

Testing Methodology Variations

• Different trials have used varying HRD score cutoffs (≥33 in VELIA versus ≥42 in PRIMA and PAOLA-1), complicating interpretation. 1
• HRD testing was not used as a stratification factor in all major trials, limiting the strength of subgroup analyses. 1

Practical Clinical Approach

Initial Assessment Requirements

• BRCA1/2 mutation testing (germline and/or somatic) and HRD status testing should be carried out at primary diagnosis to inform systemic therapy decisions. 1
• Testing should be performed on adequate tumor tissue obtained through biopsy or surgical resection. 1

Treatment Sequencing for HRD-Negative Patients

• Primary cytoreductive surgery followed by platinum-based chemotherapy remains the preferred approach when complete cytoreduction is achievable. 1
• Neoadjuvant chemotherapy (3-4 cycles) followed by interval cytoreductive surgery is appropriate when complete resection is unlikely or for poor surgical candidates. 1
• Bevacizumab addition to chemotherapy and as maintenance provides the most established benefit in HRD-negative populations. 1

Monitoring and Follow-Up

• Progression-free survival and overall survival should remain primary endpoints when evaluating treatment efficacy. 1
• Post-treatment progression data and PFS2 should be considered key secondary endpoints, as PARP inhibitors may impact effectiveness of subsequent treatments. 1

Important Caveats

Population-Specific Considerations

• The magnitude of PARP inhibitor benefit in HRD-negative patients is substantially lower than in BRCA-mutated or HRD-positive populations, with overlapping confidence intervals suggesting limited discriminatory ability. 1
• Selection for clinical trials should consider disease burden, pace of disease progression, prior treatment response, and patient performance status. 1

Emerging Evidence Gaps

• Better biomarkers are urgently needed to identify current homologous recombination proficiency status and stratify HGSC management more effectively. 1
• The optimal sequence of therapies for HRD-negative patients remains an area requiring further investigation through clinical trials. 1