EVIDENCE CONTINUES to mount for the benefits of poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer. Rucaparib (Rubraca) maintenance therapy after response to platinum-containing therapy significantly improved progression-free survival in patients with recurrent ovarian cancer compared with placebo, according to the results of the ARIEL3 trial presented at the 2017 European Society for Medical Oncology (ESMO) Congress and published recently in The Lancet.¹ 

Progression-free survival was significantly improved compared with placebo in all three study populations: 

• Patients with a germline or somatic BRCA mutation (by 11.2 months)
• Patients with a BRCA mutation or those with BRCA wild-type (by 8.2 months) determined to be homologous recombination deficient 
• All patients studied (intent-to-treat population) (by 5.4 months).

“The most robust improvement was observed in the BRCA-mutated group, with a 77% reduction in the risk of progression or death with rucaparib vs placebo, but improvement in progression-free survival was seen across all three subgroups evaluated. These results reinforce rucaparib’s potential to provide an enduring and significant clinical benefit in women with advanced ovarian cancer, regardless of their tumor genetics,” said lead author Jonathan Ledermann, MD, Professor of Medical Oncology, UCL Cancer Institute, London. 

Jonathan Ledermann, MD

“It is both impressive and encouraging that rucaparib demonstrated improvements in key primary, secondary, and exploratory endpoints in all three ARIEL3 populations. It is also clinically significant that rucaparib not only sustained patients’ most recent responses to platinum, but in some participants also enhanced that response, including the radiologic elimination of residual tumor,” Dr. Ledermann continued. 

Rucaparib is approved by the U.S. Food and Drug Administration (FDA) as monotherapy for patients with BRCA mutation (germline and/or somatic)-associated advanced ovarian cancer previously treated with two or more chemotherapy lines. According to a press release, Clovis Oncology, the manufacturer of rucaparib, plans to submit a supplemental New Drug Application to the FDA based on the ARIEL3 findings for a second-line or later maintenance treatment indication for ovarian cancer. 

Study Details and Findings 

ARIEL3 IS A DOUBLE-BLIND, placebo-controlled phase III trial of rucaparib that enrolled 564 women with platinum-sensitive, high-grade ovarian, fallopian tube, or primary peritoneal cancer. Primary efficacy was evaluated in three predefined molecular subgroups: BRCA-mutated (n = 196); homologous recombination– deficient (n = 354); and intent to treat (n = 564). 

Rucaparib reduced the risk of disease progression by 77% in BRCA-mutant patients. Median progression-free survival in this group was 16.6 months for rucaparib vs 5.4 months for placebo (P < .0001). In the homologous recombination–deficient subpopulation, median progression-free survival was 13.6 months for rucaparib vs 5.4 months for placebo (P < .0001). In the overall intent-to-treat analysis, rucaparib reduced the risk of disease progression by 64%, with a median progression-free survival of 10.8 months for rucaparib vs 5.4 months for placebo (P < .0001). In the blinded independent central review analysis of progression-free survival, the results similarly favored rucaparib. 

“These results reinforce rucaparib’s potential to provide an enduring and significant clinical benefit in women with advanced ovarian cancer, regardless of their tumor genetics.”

— Jonathan Ledermann, MD

Tweet this quote

An exploratory analysis of progression-free survival was conducted in BRCA wild-type patients with loss of heterogeneity-high and loss of heterogeneity-low patients (n = 158 and 161, respectively). In this analysis, rucaparib significantly improved median progression-free survival for both subgroups. 

“We had hoped the loss of heterogeneity test would distinguish responders from nonresponders, but both high and low loss of heterogeneity groups benefited,” Dr. Ledermann told the audience. “However, the magnitude of progression-free survival benefit was greater in the BRCA wild-type/loss of heterogeneity–high patients.” 

According to the investigator review, in the loss of heterogeneity–high group, median progression-free survival was 9.7 months with rucaparib vs 5.4 months with placebo (P < .0001). In the loss of heterogeneity–low group, median progression-free survival was 6.7 months and 5.4 months, respectively (P < .0049). 

Safety Analysis 

THE MOST COMMON GRADE 3 or higher treatment-emergent events with rucaparib were anemia/decreased hemoglobin (19%), increase in the levels of alanine transaminase/aspartate transaminase (10%), neutropenia (7%), asthenia/fatigue (7%), thrombocytopenia (5%), vomiting (4%), and nausea (4%). Treatment discontinuation due to treatment-emergent adverse events was 13.4% in the rucaparib arm vs 1.6% in the placebo group. Three patients treated with rucaparib developed treatment-emergent myelodysplastic syndrome/acute myeloid leukemia vs no patients in the placebo arm. 

Further Commentary 

Andrés Poveda, MD

COMMENTING ON THE ARIEL3 TRIAL results, ESMO expert Andrés Poveda, MD, Head of the Gynecological Cancer Clinic, Oncology Foundation Institute, Valencia, Spain, and Chair of the Gynecologic Cancer Intergroup, said: “ARIEL3 achieved a huge decrease in the risk of relapse with rucaparib. All of the patient subgroups benefited, especially those with BRCA mutations, but also those with [homologous recombination deficiency].” 

Dr. Poveda noted that the addition of rucaparib as maintenance therapy would extend the population of patients who benefit from PARP inhibition. “Further studies are needed to identify biomarkers of response to PARP inhibitors, specifically whether there are non–[homologous recombination deficiency] factors that predict response,” he noted. ■

DISCLOSURE: Dr. Ledermann is on the advisory boards of and is an invited speaker for Clovis Oncology, AstraZeneca, and Pfizer. Dr. Poveda reported no conflicts of interest. 

REFERENCE 

1. Coleman RL, Oza AM, Lorusso D: ARIEL3: Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. September 12, 2017 (early release online).