In the historic city of Xi'an, renowned for its cultural significance, the 2024 Chinese Congress of Holistic Integrative Oncology (CCHIO) and the Asian Oncology Society (AOS) took place from November 14 to 17, creating a global platform for the oncology community. During the CCHIO’s gynecological oncology session, Dr. Jianqing Zhu from Zhejiang Cancer Hospital presented her report on "Precision Diagnosis and Treatment of Platinum-Resistant Recurrent Ovarian Cancer."

Challenges in Treating Platinum-Resistant Ovarian Cancer

The majority of ovarian cancer patients experience recurrence or progression, eventually developing resistance to platinum-based therapies. Despite advancements in treatment, the median survival for these patients remains limited, and therapeutic options are scarce. Strategies for treating platinum-resistant recurrent epithelial ovarian cancer include non-platinum chemotherapy, anti-angiogenic agents, PARP inhibitors, immunotherapy, and targeted therapies.

Non-Platinum Chemotherapy

Several phase III studies have indicated that while multiple chemotherapeutic agents are available, the optimal choice remains uncertain. Second-line therapy typically involves single-agent non-platinum chemotherapy, with response rates of 10–20%, median progression-free survival (PFS) of 3–4 months, and median overall survival (OS) of 9–12 months. Combination chemotherapy does not enhance efficacy but increases toxicity.

Anti-Angiogenic Agents: Bevacizumab

The AURELIA trial, a phase III study involving 361 patients, compared single-agent non-platinum chemotherapy (e.g., paclitaxel, liposomal doxorubicin, or topotecan) with chemotherapy plus bevacizumab. The combination significantly improved PFS (HR = 0.48; P ≤ 0.001), though no significant OS difference was observed (HR = 0.85; P ≤ 0.174). The objective response rate (ORR) increased from 11.8% with chemotherapy alone to 27.3% with the addition of bevacizumab.

PARP Inhibitors

Studies such as Study42, Study10, ARIEL2, and QUADRA demonstrated the efficacy of PARP inhibitors (e.g., olaparib, niraparib, rucaparib) in platinum-resistant ovarian cancer with BRCA mutations after two or more lines of chemotherapy. However, as OS data emerge, questions arise regarding their long-term value.

Recent research on highly selective PARP inhibitors, such as Saruparib (AZD5305), shows greater efficacy than first-generation inhibitors. Ongoing trials, including the IMP1734 study, aim to evaluate the safety and efficacy of PARP1-selective inhibitors in advanced tumors.

Immunotherapy (PD-1/PD-L1 Antibodies)

Currently, immune checkpoint inhibitors show limited efficacy in ovarian cancer, possibly due to its unique immune microenvironment. While PD-L1 expression serves as a biomarker in other cancers, its role in ovarian cancer remains unclear. Pan-tumor biomarkers like dMMR/MSI-H and TMB-H may offer insights into immunotherapy response.

Antibody-Drug Conjugates (ADCs)

ADCs have gained attention in the treatment of platinum-resistant ovarian cancer. Mirvetuximab soravtansine (MIRV), the first FDA-approved ADC for this indication, targets folate receptor-α (FRα). The MIRASOL trial demonstrated that MIRV improves both PFS and OS compared to chemotherapy in FRα-positive patients, with fewer adverse events. It is now recommended as a standard treatment for FRα-positive cases.

Other ADCs, such as trastuzumab deruxtecan for HER2-positive patients, and ADCs targeting CDH6 and TROP2, are under investigation.

Oncology Frontier: For patients with platinum-resistant recurrent ovarian cancer, especially in the post-PARP inhibitor era, what treatment strategies are recommended by current guidelines?

Dr. Jianqing Zhu: Guidelines emphasize supportive care, including palliative treatment, nutritional support, and symptom management, as many patients have lost the chance for a cure. Managing pain and improving quality of life become crucial when tumor control is no longer achievable.

For chemotherapy, non-platinum single-agent regimens are recommended, as platinum-based combinations do not improve outcomes but increase toxicity. Adding bevacizumab to non-platinum regimens offers better results.

Additionally, genetic testing can reveal actionable mutations, enabling targeted therapy for select patients.

• Oncology Frontier: What emerging precision therapies show promise for platinum-resistant ovarian cancer?

Dr. Jianqing Zhu: In the post-PARP inhibitor era, ADCs have gained significant attention. The FRα-targeting ADC MIRV has shown improved PFS and OS in FRα-positive cases compared to chemotherapy. Other ADCs, such as trastuzumab deruxtecan for HER2-positive patients, and those targeting CDH6 and TROP2, are being actively researched.

• Oncology Frontier: Can secondary cytoreductive surgery benefit these patients? What role does surgery play in their treatment?

Dr. Jianqing Zhu: Secondary cytoreductive surgery is generally not recommended for platinum-resistant cases due to the lack of effective postoperative chemotherapy options. However, small retrospective studies suggest surgery may be feasible for isolated or oligometastatic recurrences, though survival benefits remain unproven.

Surgery is also essential for managing complications like bowel obstruction, perforation, or hemorrhage.

Future Directions in Platinum-Resistant Ovarian Cancer Treatment

• Combination Therapies: Enhanced understanding of resistance mechanisms is driving combination approaches, such as immunotherapy plus targeted therapies.
• Personalized Medicine: Genomic analyses and biomarker testing will guide treatment decisions, enabling tailored approaches for each patient.
• Biomarker-Guided Therapy: Advances in molecular characterization, such as TP53 mutations, are facilitating precision therapies. For instance, WEE1 inhibitors like adavosertib, combined with chemotherapy, show promise in prolonging PFS.

Conclusion

Professor Zhu emphasized the critical need for innovative therapies and biomarker-driven strategies to address the challenges of platinum-resistant ovarian cancer. With advancements in ADCs and combination therapies, the future of precision oncology offers new hope for these patients.

About Dr. Jianqing Zhu

• Director: Gynecologic Oncology Surgery, Zhejiang Cancer Hospital
• Chief Physician
• Vice-Chairperson: Ovarian Cancer Committee, China Anti-Cancer Association
• Standing Committee Member: CSCO Gynecologic Oncology Expert Committee
• Vice-Chairperson: Ovarian Cancer Quality Control Expert Committee, National Cancer Center
• Committee Member: Cervical Cancer Quality Control Expert Committee, National Cancer Center
• Vice-Chairperson: Gynecologic Oncology Medical Education Committee, China Medical Education Association