Ovarian Cancer: Optimizing Therapy in HRD – From BRCA-Adjusted Surgery to Maintenance Strategies

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Ovarian Cancer Maintenance Therapy: Reshaping Treatment Paradigms

Welcome to an in-depth presentation exploring the critical role of maintenance therapy in guiding the treatment of ovarian cancer. This session will provide you with a comprehensive understanding of how molecular profiles are transforming therapeutic approaches and improving patient outcomes. You will discover the latest insights into identifying patients who will benefit most from targeted therapies, particularly PARP inhibitors and other evolving strategies.

Evolution of Maintenance Therapy

The presentation begins by detailing the evolution of ovarian cancer treatment, highlighting how chemotherapy with agents like carboplatin and paclitaxel became the standard of care for initial therapy. You will learn how maintenance chemotherapy, while showing some promise in prolonging progression-free survival, did not consistently translate into overall survival benefits. The introduction of molecularly targeted therapies, such as bevacizumab, marked a significant shift, demonstrating improved progression-free survival when added to chemotherapy. This laid the groundwork for a new era of maintenance treatment.

Targeting DNA Repair with PARP Inhibitors

A significant portion of this discussion is dedicated to PARP inhibitors and their role in targeting Homologous Recombination Deficiency (HRD), a key DNA repair pathway. You will learn about:

• The mechanism of PARP inhibitors, which exploit the reliance of cancer cells with HRD (e.g., BRCA mutations) on error-prone pathways, leading to DNA damage accumulation and cell death.
• The concept of HRD, which encompasses not only BRCA mutations but also other genetic alterations in the HRR pathway.
• Early studies that demonstrated the effectiveness of PARP inhibitor maintenance therapy in platinum-sensitive relapsed ovarian cancer, particularly in patients with BRCA mutations.
• The expansion of PARP inhibitor use as maintenance therapy following front-line treatment, showing benefits across broader patient populations, including those with and without BRCA mutations.
• The importance of clinically validated detection of HRD, including BRCA mutation testing and scoring of genomic instability.
  
  

Combining Therapies for Enhanced Outcomes

The presentation explores the rationale and impact of combining PARP inhibitors with other agents, such as anti-angiogenic therapy (e.g., bevacizumab) and immune checkpoint inhibitors. Key aspects of combination strategies include:

• Preclinical models suggesting synergy between PARP inhibitors and immune checkpoint inhibitors, regardless of BRCA or PD-L1 status.
• The immunosuppressive effects of VEGF in the tumor microenvironment and how anti-angiogenic therapy can reverse these, potentially enhancing immune responses.
• Ongoing investigations into various combination strategies in the front-line setting for ovarian cancer.
  
  

HRD Status and Surgical Considerations

The discussion extends to the potential implications of HRD status for surgical treatment in ovarian cancer. You will learn about:

• Initial data suggesting that HRD-positive ovarian cancers may exhibit different growth characteristics, including more nodular peritoneal implants and less infiltrative peritoneal lesions, potentially making them easier to resect.
• Retrospective studies indicating higher complete surgical resection rates in BRCA-mutated ovarian cancers.
• The ongoing debate on whether complete resection to no visible residual disease is as critical in HRD-positive cancers as it is in HRD-negative cases.
• Evidence suggesting that secondary cytoreductive surgery can improve post-recurrence survival, particularly in BRCA-mutated women, even when followed by PARP inhibitor maintenance.
  
  

Challenges, Future Directions, and Personalized Care

The presentation also addresses critical considerations and future directions in maintenance therapy for ovarian cancer. Key takeaways include:

• Maintenance PARP inhibitor treatment has dramatically shifted the paradigm in advanced ovarian cancer.
• While significant benefits are observed, a large number of patients do not experience major benefits from maintenance PARP inhibitors, and immune checkpoint inhibitors have not yet provided substantial incremental gains in progression-free survival in this setting.
• The landscape of maintenance options at recurrence is reduced with increased use of PARP inhibitors in the front-line setting.
• Personalized first-line maintenance treatment is crucial, considering factors beyond biomarkers, such as platinum responsiveness, patient characteristics, and individual preferences.
• The importance of assessing platinum responsiveness and HRD status, potentially after a few cycles of chemotherapy, as key predictive indicators of PARP inhibitor benefit.
• Ongoing research into antibody-drug conjugates (ADCs) as a potential new frontier to address unmet needs in maintenance therapy.
• The acknowledgment that while HRD testing has a prognostic and predictive role, inconclusive or borderline results can occur, highlighting the need for continued refinement of testing methodologies.
• The importance of recognizing that cross-trial comparisons have inherent limitations due to differences in eligibility, interventions, endpoints, and follow-up durations.
• The understanding that exploratory endpoints are hypothesis-generating and not intended to guide clinical practice directly.

This comprehensive overview is designed to equip you with the knowledge needed to navigate the complexities of maintenance therapy and contribute to optimizing patient experience and outcomes in ovarian cancer.