What is the recommended treatment strategy, including surgery, chemotherapy, and maintenance therapy, for a woman with ovarian cancer who is BRCA‑negative (no germline BRCA mutation) but HRD‑positive (homologous recombination deficiency positive)?

Treatment of BRCA-Negative, HRD-Positive Ovarian Cancer

For women with BRCA-negative but HRD-positive advanced ovarian cancer who achieve complete or partial response to first-line platinum-based chemotherapy, niraparib maintenance for 3 years is the primary recommended option, with olaparib plus bevacizumab for 2 years as an alternative if bevacizumab was used in first-line treatment. 1

Initial Treatment Approach

Surgery and Chemotherapy

• Complete primary cytoreductive surgery (achieving no visible residual disease) followed by six cycles of paclitaxel 175 mg/m² plus carboplatin AUC 5-6 every 3 weeks is the standard backbone regimen 1, 2
• For high-risk disease (stage IV or suboptimal cytoreduction), add bevacizumab 15 mg/kg to chemotherapy and continue as maintenance, which improves progression-free survival with an ESMO-MCBS score of 4 1, 2
• Neoadjuvant chemotherapy for three cycles followed by interval cytoreductive surgery is appropriate when complete primary cytoreduction is not feasible 1

Mandatory Molecular Testing

• All patients must undergo BRCA1/2 mutation testing (germline and somatic) plus HRD status assessment at diagnosis before selecting maintenance therapy 1, 2
• HRD testing should use a validated assay such as Myriad myChoice CDx 1, 3

Maintenance Therapy for BRCA-Negative, HRD-Positive Disease

Primary Recommendation

Niraparib 200-300 mg daily for 3 years is the preferred maintenance option for BRCA-wild-type/HRD-positive patients who achieve complete or partial response to first-line platinum-based chemotherapy 1, 2

• This recommendation has ESMO-MCBS v1.1 score of 3 and ESCAT score of I-A 1
• The PRIMA trial demonstrated significant PFS benefit in the HRD-positive subgroup without BRCA mutations 1

Alternative Option

Olaparib 300 mg twice daily plus bevacizumab 15 mg/kg every 3 weeks for 2 years is recommended if bevacizumab was included in first-line chemotherapy 1, 2

• This combination has ESMO-MCBS v1.1 score of 3 and ESCAT score of I-A 1
• The PAOLA-1 trial showed pronounced PFS benefit in HRD-positive patients treated with olaparib plus bevacizumab maintenance 1
• Critically, patients with HRD-negative tumors showed no benefit (HR 1.00; 95% CI 0.75-1.35), making HRD testing essential 1, 3

If Bevacizumab Contraindicated

• Niraparib monotherapy remains the recommended option for HRD-positive, BRCA-negative patients 1
• Bevacizumab alone can be considered for HRD-negative tumors 1

Treatment Algorithm by Clinical Scenario

Scenario 1: First-Line Chemotherapy WITHOUT Bevacizumab

• Confirm HRD-positive status → Niraparib 3 years (Category 1) 1, 2

Scenario 2: First-Line Chemotherapy WITH Bevacizumab

• Confirm HRD-positive status → Choose between:
  • Olaparib + bevacizumab for 2 years (preferred if tolerating bevacizumab) 1
  • Niraparib alone for 3 years (alternative) 1

Scenario 3: Complete Response with No Evidence of Disease

• Same maintenance recommendations apply; do not simply observe 1, 2

Critical Warnings and Pitfalls

Do NOT Use Olaparib Monotherapy

• Olaparib as single-agent maintenance is NOT FDA-approved for BRCA-negative patients, even if HRD-positive 1, 3
• Olaparib monotherapy is only approved for BRCA-mutated (germline or somatic) disease 1
• For HRD-positive/BRCA-negative patients, olaparib must be combined with bevacizumab 1

HRD Testing is Mandatory

• Never initiate PARP inhibitor therapy without confirmed HRD status in BRCA-negative patients 1, 2, 3
• HRD-negative patients derive no benefit from olaparib combinations and should receive bevacizumab alone or niraparib 1

Duration Matters

• Niraparib is given for 3 years, while olaparib combinations are given for 2 years 1
• Continue until disease progression, unacceptable toxicity, or completion of planned duration 1, 2

Toxicity Management

• PARP inhibitor toxicity is manageable through dose reductions and treatment interruptions 1
• Monitor for rare but serious risks including AML/MDS with prolonged PARP inhibitor exposure 1

Recurrent Disease Considerations

Platinum-Sensitive Recurrence (≥6 months after platinum)

• After response to platinum-based chemotherapy, maintenance with PARP inhibitors (olaparib, niraparib, or rucaparib) is strongly recommended regardless of BRCA status 1, 4
• The magnitude of benefit remains greatest in BRCA-mutated patients but is still significant in HRD-positive patients 1

Platinum-Resistant Recurrence

• PARP inhibitors are not FDA-approved as monotherapy for platinum-resistant disease 5
• Weekly paclitaxel plus bevacizumab is the preferred option (ESMO-MCBS 4) 2, 5

Evidence Quality Note

The recommendations prioritize the most recent ESMO 2023 guidelines 1 and ASCO 2020 guidelines 1, which provide Level I evidence with Grade A strength of recommendation for PARP inhibitor maintenance in HRD-positive disease. The PRIMA and PAOLA-1 trials specifically demonstrated benefit in the BRCA-wild-type/HRD-positive subgroup, making this a well-established treatment paradigm 1.