What are the next treatment options for a patient with high-grade serous carcinoma (HGSC), BRCA negative, homologous recombination deficiency (HRD) negative, who has received 6 rounds of carboplatin (carbo)/paclitaxel (taxol), debulking surgery, 2 more rounds of chemotherapy with Avastin (bevacizumab) and then Avastin (bevacizumab) for maintenance, and has experienced recurrence at 6 months?

Treatment Options for Platinum-Resistant High-Grade Serous Carcinoma

This patient has platinum-resistant disease (recurrence at 6 months) that is BRCA-negative and HRD-negative, which represents a particularly challenging clinical scenario with limited effective options; the best approach is non-platinum chemotherapy with single-agent paclitaxel, pegylated liposomal doxorubicin, or topotecan, recognizing that response rates will be poor (≤10%) and median survival approximately 4-5 months.

Disease Classification and Prognosis

This patient's recurrence at 6 months after completing platinum-based therapy defines platinum-resistant disease, which carries a significantly worse prognosis than platinum-sensitive disease 1. The absence of BRCA mutations and HRD negativity further limits therapeutic options, as this patient cannot benefit from PARP inhibitor therapy 1, 2.

• Expected response rates to subsequent chemotherapy are poor (≤10%) in platinum-resistant disease 1
• Median survival with older regimens is only 4-5 months, though newer agents may offer modest improvements 1
• The molecular profile (BRCA-negative/HRD-negative) suggests inherent resistance to DNA-damaging agents and excludes targeted maintenance strategies 2

Recommended Treatment Algorithm

First-Line Options for Platinum-Resistant Disease

Single-agent non-platinum chemotherapy is the standard approach, with the following options:

• Weekly paclitaxel (80 mg/m²) is preferred for BRCA wild-type patients, as it demonstrated superior progression-free survival (14.3 months) compared to other doublets in platinum-sensitive relapse 3
• Pegylated liposomal doxorubicin is an alternative option, though it showed inferior outcomes (11.8 months PFS) in BRCA wild-type patients compared to paclitaxel 3
• Topotecan (either oral or intravenous) can be considered, with attenuated dosing (lower than 1.5 mg/m² for 5 days) recommended to reduce toxicity while maintaining efficacy 1

Critical Decision Point: Avoid Platinum Re-challenge

• Do not re-introduce carboplatin/paclitaxel doublet therapy at this time, as the 6-month recurrence interval defines platinum resistance with expected response rates ≤10% 1
• Platinum-free regimens are more appropriate for this molecular profile, particularly given potential BRCA2 amplification patterns that can confer extreme platinum resistance 4

Bevacizumab Continuation Considerations

Bevacizumab should likely be discontinued in this setting:

• The patient already received bevacizumab during primary treatment and maintenance, and disease progressed on therapy 1
• Progression on bevacizumab maintenance suggests resistance to anti-angiogenic therapy 2
• Combining bevacizumab with single-agent chemotherapy in platinum-resistant disease has limited supporting evidence 1

Monitoring and Response Assessment

• Perform CT chest/abdomen/pelvis with contrast after every 2-3 cycles to assess response 1
• Monitor complete blood counts before each cycle, with platelet count ≥100,000/mm³ and ANC ≥1,000/mm³ required for safe chemotherapy administration 5
• Consider G-CSF support for subsequent cycles if neutropenia develops 5, 6

Clinical Trial Enrollment

Strongly encourage enrollment in a clinical trial given the poor prognosis and limited standard options 1:

• Novel agents under investigation include immune checkpoint inhibitors, PI3K inhibitors, Wee1 kinase inhibitors, and ATR inhibitors specifically for platinum-resistant disease 2
• Antibody-drug conjugates represent promising new approaches for chemoresistant HGSOC 2
• Clinical trials may offer access to combination strategies not available in standard practice 1

Common Pitfalls to Avoid

• Premature platinum re-challenge: Reintroducing carboplatin at 6 months will yield minimal benefit and expose the patient to unnecessary toxicity 1
• Continuing ineffective bevacizumab: Progression on bevacizumab maintenance indicates resistance; continuing it adds toxicity without benefit 2
• Overlooking supportive care: With median survival of 4-5 months, early integration of palliative care and symptom management is essential 1
• Inadequate toxicity monitoring: Single-agent chemotherapy still requires careful monitoring for myelosuppression, with dose reductions or growth factor support as needed 5, 6

Alternative Considerations

If the patient has excellent performance status and desires more aggressive therapy:

• Gemcitabine monotherapy can be considered, though it showed inferior outcomes (9.8 months PFS) compared to paclitaxel in BRCA wild-type patients 3
• Combination chemotherapy (non-platinum doublets) may be considered but will increase toxicity without clear survival benefit in this platinum-resistant, biomarker-negative population 3