Can olaparib (PARP inhibitor) be used to treat a female patient with BRCA (Breast Cancer Gene)-mutated ovarian cancer who has developed resistance to platinum-based chemotherapy?

Olaparib in Platinum-Resistant BRCA-Mutated Ovarian Cancer

Olaparib is NOT recommended for platinum-resistant BRCA-mutated ovarian cancer outside of a clinical trial, as PARP inhibitors have less than 5% activity in this setting and current approvals are restricted to platinum-sensitive disease. 1

Current Regulatory Status and Evidence

FDA and EMA Approvals

• Olaparib is FDA-approved only for patients with germline BRCA-mutated ovarian cancer who have received ≥3 prior lines of chemotherapy, but this approval does not specify platinum resistance status 1
• In Europe, the EMA license for PARP inhibitor monotherapy (rucaparib specifically) is explicitly restricted to patients with 'platinum-sensitive' disease, not platinum-resistant disease 1
• The ASCO guideline explicitly states that PARP inhibitor treatment is not generally recommended for platinum-resistant cancer 1

Evidence Base for Platinum-Resistant Disease

• PARP inhibitors demonstrate <5% activity for treatment of BRCA wild-type, platinum-resistant, recurrent ovarian cancer 1
• While early Phase II data (NCT00628251) showed some activity of olaparib capsules versus pegylated liposomal doxorubicin in platinum-resistant or partially platinum-sensitive disease, this did not translate into regulatory approval for this indication 2
• The SOLO3 trial specifically enrolled patients with platinum-sensitive relapsed ovarian cancer, not platinum-resistant disease, and demonstrated superior outcomes (ORR 72.2% vs 51.4%, median PFS 13.4 vs 9.2 months) 2

Where Olaparib IS Indicated

Platinum-Sensitive Recurrent Disease

• PARP inhibitors (olaparib, niraparib, rucaparib) are strongly recommended as maintenance therapy following response to platinum-based second or higher line treatment in platinum-sensitive disease (Level I evidence, Grade A recommendation) 1
• The benefit is greatest in patients with BRCA mutations but extends to those without BRCA mutations 1, 3
• Four major trials (Study 19, SOLO2, NOVA, ARIEL3) demonstrated 62-68% reduction in risk of progression or death (HR 0.32-0.38) in platinum-sensitive disease 3

Treatment Setting (Not Maintenance)

• PARP inhibitors can be considered as monotherapy in BRCA-mutated patients (Level III evidence, Grade B recommendation), but regulatory restrictions apply 1
• Olaparib showed superior response rates compared to non-platinum chemotherapy in platinum-sensitive disease (84.6% vs 61.5% in patients with 2 prior lines) 2

Critical Clinical Pitfalls

Platinum Sensitivity Definition

• The traditional 6-month platinum-free interval cutoff for defining platinum sensitivity has been abandoned by consensus conferences as it has significant limitations 1
• True platinum resistance is defined as progressive disease during or immediately after platinum therapy, not simply a short platinum-free interval 1

Post-Progression Considerations

• Real-world data suggest cross-resistance between olaparib and subsequent chemotherapy, with response rates of only 22.2%, 11.1%, and 9.5% for platinum-free intervals >12 months, 6-12 months, and <6 months respectively 4
• Re-treatment with PARP inhibitors after progression on prior PARP inhibitor therapy is not recommended, as there are no data supporting benefit 1

Recommended Approach for Platinum-Resistant Disease

If your patient has platinum-resistant BRCA-mutated ovarian cancer:

• Enroll in a clinical trial investigating PARP inhibitors in combination with chemotherapy, antiangiogenesis agents, or immunotherapy 1
• Consider standard non-platinum chemotherapy options (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan) 2
• Reserve olaparib for if/when the patient achieves platinum-sensitive status again after responding to subsequent platinum rechallenge 1, 3