The PARP inhibitor rucaparib can extend progression-free survival (PFS) in relapsed ovarian cancer with deleterious mutations but outcomes in advanced disease are still poor.
The open-label ARIEL-4 study conducted across 12 countries randomised 349 women with relapsed BRCA1-mutated or BRCA2-mutated ovarian carcinoma to either oral rucaparib or chemotherapy.
Patients in the chemotherapy group could cross over to rucaparib at disease progression.
The women, with a median age of 58 years, had previously received at least two chemotherapy regimens. Half the patients (51%) had platinum-resistant disease, 28% had partially platinum-sensitive disease, and 21% had fully platinum-sensitive disease.
After a mean follow-up of 25 months, median PFS was 7·4 months in the rucaparib group versus 5·7 months in the chemotherapy group (HR 0·64 [95% CI 0·49–0·84]; p=0·0010).
The study, published in Lancet Oncology, said a prespecified exploratory analysis of patients with BRCA reversion mutations before treatment found they were less likely to benefit from rucaparib.
It found median PFS was 2·9 months in the rucaparib group versus 5·5 months in the chemotherapy group (HR 2·77).
“Reversion mutations in [homologous recombination repair] HRR genes such as BRCA1 and BRCA2 have also been observed as a resistance mechanism for other PARP inhibitors, including olaparib and talazoparib,” the study said.
“These data suggest a gap in commercial tests for BRCA reversion mutations to enable pretreatment genomic disease characterisation.”
An accompanying Comment article said the overall PFS in both groups was “disappointingly short”.
“They show that rucaparib is active and a reasonable alternative to chemotherapy for women with advanced, pretreated, BRCA1/2-mutated ovarian cancer. However, they do not show that rucaparib is overwhelmingly superior to rechallenge platinum.”
The author said optimising first-line therapy still trumps all other efforts.
“Advanced pretreated ovarian cancer has a poor prognosis; PARP inhibitor therapy does not change that radically enough.”
“That means a major global challenge: to provide women with high-grade serous or high-grade endometrioid ovarian cancer with access not only to appropriate surgical expertise and platinum chemotherapy, but also to BRCA1/2 and HRD testing at diagnosis and to early post-chemotherapy PARP inhibitor therapy if they are expected to benefit from it.”
The ARIEL-4 study found no new safety signals compared to the expected safety profiles for PARP inhibitors.
The most common serious treatment-emergent adverse event (TEAE) was anaemia and treatment interruption and/or dose reduction due to any TEAE occurred in 50% of patients in the rucaparib group and 44% of patients in the chemotherapy group.
Three deaths as a result of TEAEs were considered to be potentially related to rucaparib – a cardiac disorder, one myelodysplastic syndrome, and one unconfirmed cause.