Recent advances in combination therapies involving PARP inhibitors are showing promising results for ovarian cancer treatment, offering new hope for patients with both PARP-resistant and PARP-sensitive disease.
Emerging Combination Strategies
Research has identified several promising combination approaches with PARP inhibitors. The CAPRI trial, evaluating the ATR inhibitor ceralasertib with olaparib, demonstrated a 48% response rate in patients with acquired PARP inhibitor resistance. Similarly, the phase II EFFORT trial studying the WEE1 inhibitor adavosertib combined with olaparib showed encouraging activity with response rates of 29% in the combination arm.
Antiangiogenic Combinations
The combination of PARP inhibitors with antiangiogenic agents has produced mixed results. While early phase II trials showed promise, particularly in BRCA wild-type patients, the phase III GY004 trial comparing cediranib plus olaparib to standard chemotherapy did not meet its primary endpoint. However, the PAOLA trial demonstrated significant benefits when adding olaparib to bevacizumab maintenance therapy, specifically in BRCA-mutated and HRD cohorts.
Immunotherapy Partnerships
Emerging data suggests potential synergy between PARP inhibitors and immune checkpoint inhibitors. The MEDIOLA phase II trial reported a 71.9% response rate with olaparib plus durvalumab in BRCA-mutated platinum-sensitive ovarian cancer. Multiple phase III trials are currently ongoing to further evaluate these combinations.
Overcoming Resistance Mechanisms
Researchers have identified several mechanisms of PARP inhibitor resistance, including:
- BRCA reversion mutations
- Loss of 53BP1 expression
- Stabilization of stalled replication forks
- PI3K/AKT pathway activation
- MDR1 overexpression
- PARP1 mutations or loss
Understanding these resistance mechanisms has led to rational combination strategies targeting specific pathways to enhance PARP inhibitor efficacy.
Future Directions
Current clinical trials are exploring various combination approaches, including:
- PARP inhibitors with DNA damage response inhibitors
- Combinations with cell cycle regulators
- Integration with standard chemotherapy
- Novel immunotherapy combinations
These studies aim to optimize PARP inhibitor use in both homologous recombination deficient and proficient tumors.
The field continues to evolve rapidly, with ongoing research focused on identifying biomarkers for patient selection and developing strategies to prevent or overcome resistance. As our understanding of resistance mechanisms improves, more effective combination approaches are likely to emerge, potentially expanding the utility of PARP inhibitors in ovarian cancer treatment.
