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Subgroup Analysis of the ARIEL4 Study of the Effect of Platinum Sensitivity on Efficacy of Rucaparib versus Chemotherapy for BRCA-Mutated, Advanced, Relapsed Ovarian Carcinoma

2021 Year in Review - Ovarian Cancer

Results of the subgroup analysis of the ARIEL4 study suggest that heavily pretreated patients with advanced relapsed ovarian carcinoma harboring a BRCA1/2 mutation derive progression-free survival benefit from rucaparib treatment across all platinum-sensitivity subgroups.

The confirmatory phase 3 ARIEL4 study (NCT02855944) demonstrated that rucaparib therapy significantly improved progression-free survival (PFS), compared with chemotherapy in patients with advanced relapsed ovarian carcinoma harboring a BRCA1/2 (BRCA) mutation. Results of the prespecified exploratory analysis, which assessed the effect of platinum sensitivity on efficacy outcomes were reported at the 2021 American Society of Clinical Oncology Annual Meeting.

In the ARIEL4 study, patients with relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer, who received ≥2 previous chemotherapy regimens, and harbored germline or somatic BRCA mutations were enrolled. Eligible patients were randomized 2:1 to oral rucaparib 600 mg twice daily or chemotherapy. Chemotherapy was administered based on platinum sensitivity. Stratification was by progression-free interval (PFI) and platinum status (PFI; ≥1 to <6 months [platinum resistant]; ≥6 to <12 months [partially platinum sensitive]; ≥12 months [fully platinum sensitive]). In the chemotherapy group, patients with platinum-resistant or partially platinum-sensitive disease received weekly paclitaxel 60 to 80 mg/m2; patients with fully platinum-sensitive disease received investigator’s choice of platinum-based chemotherapy (single-agent carboplatin or cisplatin, or platinum doublet). The study design allowed crossover from chemotherapy to rucaparib following radiologic disease progression. Efficacy end points were assessed in patients with a confirmed BRCA mutation. The data cutoff date was September 30, 2020.

Subgroup analysis showed that patients receiving rucaparib had comparable or longer PFS across all platinum status subgroups, compared with those receiving chemotherapy (platinum-resistant: 6.4 vs 5.7 months, hazard ratio, 0.78; partially platinum-sensitive: 8.0 vs 5.5 months, hazard ratio, 0.40; fully platinum-sensitive: 12.9 vs 9.6 months, hazard ratio, 0.69). Similarly, patients receiving rucaparib had comparable or higher response rates across all platinum status subgroups compared with those receiving chemotherapy. In patients with platinum-sensitive disease, rucaparib showed response rates similar to those of platinum-based chemotherapy (63.6% vs 56.5%), with a trend toward a longer duration of response (10.8 months vs 7.6 months).

In the intent-to-treat population, 64% (74/116) of patients in the chemotherapy group crossed over to receive rucaparib, and 66% of the platinum-resistant cohort (39/59), 81% of the partially platinum-sensitive cohort (25/31), and 38% of the fully platinum-sensitive cohort (10/26) crossed over to receive rucaparib.

The safety profile for rucaparib across all platinum status subgroups was consistent with that previously described. In the rucaparib group, the most frequent treatment-emergent adverse events in the platinum-resistant, partially platinum-sensitive, and fully platinum-sensitive subgroups (compared with chemotherapy) were anemia/decreased hemoglobin (47% vs 40%, 63% vs 27%, and 58% vs 20%, respectively) and nausea (52% vs 21%, 51% vs 23%, and 60% vs 68%, respectively).

These results suggest that heavily pretreated patients with advanced relapsed ovarian carcinoma harboring a BRCA1/2 mutation derive clinical benefit from rucaparib therapy in terms of PFS and response rates across all platinum-sensitivity subgroups.

Source: Oza AM, Lisyanskaya AS, Fedenko AA, et al. Subgroup analysis of rucaparib versus chemotherapy as treatment for BRCA-mutated, advanced, relapsed ovarian carcinoma: effect of platinum sensitivity in the randomized, phase 3 study ARIEL4. J Clin Oncol. 2021;39(suppl_15). Abstract 5517.

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