Worse Survival With Rucaparib in Trial of Recurrent, BRCA+ Ovarian Cancer

PARIS — A postmarketing study meant to support the approval of rucaparib (Rubraca) in ovarian cancer instead demonstrated worse overall survival (OS) for women with recurrent, advanced BRCA-positive disease, a researcher reported here.

The detailed findings from the so-called ARIEL4 trial provide further insight into drugmaker Clovis Oncology’s June decision to withdraw the indication for the PARP inhibitor as a third-line ovarian cancer treatment, which followed discussions with the FDA.

Median OS for patients assigned to rucaparib was 19.4 months, as compared with 25.4 months with standard chemotherapy options (HR 1.313, 95% CI 0.999-1.725), according to findings presented by Amit Oza, MD, of the Princess Margaret Cancer Centre in Toronto.

“The difference in overall survival in the intent-to-treat population is driven by the platinum-resistant subgroup,” he said at the European Society for Medical Oncology (ESMO) congress.

In this subgroup, median OS was just 14.2 months for women who initially received rucaparib and 22.2 months for those assigned to chemotherapy (HR 1.511, 95% CI 1.053-2.170). OS differences were not significantly different in the other two subgroups, yet still trended worse numerically for the patients who initially received the PARP inhibitor:

• Partially platinum-sensitive: 21.1 vs 23.2 months with chemotherapy
• Fully platinum-sensitive: 36.3 vs 47.2 months with chemotherapy

But OS was confounded by a high rate of crossover to rucaparib, said Oza, which was built into the study design of ARIEL4. In total, 69% of patients in the chemotherapy arm crossed over to the PARP inhibitor at disease progression. Women who crossed over to rucaparib had better outcomes than those who switched to other subsequent therapies.

By comparison, only 42% of patients in the rucaparib arm went on to receive subsequent therapy. “I think we need to understand this better,” said Oza.

As was previously reported, the primary analysis of ARIEL4 demonstrated a significant improvement in progression-free survival (PFS) with rucaparib for these patients with heavily pretreated BRCA-mutated ovarian cancer (7.4 vs 5.7 months; HR 0.67, 95% CI 0.52-0.86).

Late use of PARP inhibition has a “profound effect on the overall survival curves,” said ESMO discussant Jonathan Ledermann, MD, of UCL Cancer Institute at University College London.

Along with other potential confounders — including long post-progression survival and small patient subgroups — “we also need to think about whether there may be selection of resistant clones or development of resistant clones or whether monotherapy drives resistance more than maintenance therapy,” said Ledermann. “And of course, whether use of PARP inhibitors at later lines is associated with more resistance and less benefit than in earlier lines.”

ARIEL4 randomized 349 patients with BRCA-mutant, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer 2:1 to either rucaparib (600 mg twice daily) or standard chemotherapy.

For enrollment, patients needed to have received at least two prior lines of therapy, including one line of platinum-based chemotherapy. The standard chemotherapy arm involved either weekly paclitaxel (60-80 mg/m²) for patients who were resistant or only partially sensitive to platinum therapy, or otherwise a platinum-based option for those who were fully sensitive to prior platinum-based chemotherapy.

In looking at time-to-second progression (PFS2), Oza noted that no differences were seen between treatment arms for the platinum-resistant subgroup, while PFS2 favored rucaparib in women who were partially sensitive to platinum treatment.

Baseline characteristics were well balanced between the two randomized groups, said Oza. Median age was 58 years, and 95% of the women were white. Overall, 51% had platinum-resistant disease, while 28% were partially sensitive and 21% were fully sensitive to platinum chemotherapy.

No new safety signals were identified in the new analysis, with grade ≥3 adverse events (AEs) occurring in 40% of those assigned to rucaparib and 64% of those assigned to chemotherapy. Myelodysplastic syndromes or acute myeloid leukemia, an AE of special interest, was reported in 3% of patients initially randomized to the PARP inhibitor but in no patients initially treated with chemotherapy.