Analysis Gives New Insights Into Rucaparib Promise in Ovarian Cancer

Gottfried E. Konecny, MD

A new analysis of a randomized phase II trial showed PARP inhibitor rucaparib slowed progression of relapsedBRCA-mutant ovarian cancer regardless of whether the mutations were somatic or germline.

Patients with germline or somaticBRCAmutations had a median progression-free survival (PFS) of about 13 months when treated with rucaparib. Additionally, patients withBRCA1orBRCA2-mutant disease had similar PFS with the PARP inhibitor.

Patients with platinum-sensitive disease derived the most benefit from rucaparib, and PFS increased with the duration of the platinum-free interval, as reported at the Society of Gynecologic Oncology meeting in National Harbor, MD.

“Immediate prior platinum therapy does not appear to adversely affect rucaparib activity,” said Gottfried E. Konecny, MD, associate professor of Medicine at the University of California, Los Angeles. “Two randomized phase III confirmatory studies investigating single-agent rucaparib are ongoing: one in the switch maintenance setting involving patients with relapsed, platinum-sensitive high-grade ovarian cancer; the other is in the treatment setting in patients with relapsedBRCA-mutant high-grade ovarian cancer.”

The findings came from an analysis of the ARIEL2 trial, which investigated the effect of single-agent rucaparib on PFS in patients with relapsed platinum-sensitive ovarian cancer and objective response rate (ORR) in patients with relapsed, heavily pretreated ovarian cancer. The primary objective was to determine the response rate and PFS in patients with germline or somaticBRCAmutations and examine the effect of platinum sensitivity status and prior lines of therapy on the endpoints.

The subgroup withBRCA-mutant ovarian cancer was comprised of 134 patients who had a median age of 60 and ECOG performance status of 0 or 1. Konecny said 58% of the patients hadBRCAgermline mutations, 17.2% had somatic mutations, and 24.6% had mutations of uncertain origin. About two thirds of the patients hadBRCA1mutations and one-third hadBRCA2mutations.

Approximately three-fourths of the patients had received 3 or more prior lines of therapy, including 2 prior lines of platinum-based therapy in 39% of patients and 3 or more prior lines of platinum therapy in 46%. With regard to platinum sensitivity status, 53% of the patients had platinum-sensitive disease, and most had no intervening therapies. An additional 37% had platinum-resistant disease and 10% had platinum-refractory disease.

In the platinum-sensitive subgroup, patients who had received no intervening nonplatinum regimens had an ORR of 70%, as compared with 43% in patients who had received 1 or more nonplatinum therapies. Platinum-resistant patients had an ORR of 25%, whereas no patients with platinum-refractory disease responded to rucaparib. Disease control rates were 81% in platinum-sensitive patients with no intervening therapies, 57% with platinum-sensitive patients and prior nonplatinum therapy, 39% in the platinum-resistant subgroup, and 29% in the patients with platinum-refractory disease.

Among all patients withBRCA-mutant disease, those with platinum-sensitive disease and no nonplatinum intervening therapy had a median PFS of 12.7 months, declining to 7.4 months in the subgroup with platinum-sensitive disease and exposure to nonplatinum therapies. The platinum-resistant and refractory subgroups had median PFS of 7.3 and 5.0 months, respectively.

Among patients with platinum-sensitive disease and no prior nonplatinum therapy, the median PFS increased with the duration of platinum-free interval (PFI): 12.7 months with a PFI ³6 months, 16.9 months with a PFI ³12 months, and 25.1 months with a PFI ³18 months. Prior exposure to nonplatinum therapy reduced the median PFS to 7.4 months.

Patients withBRCAgermline or somatic mutations had almost identical median PFS, whereas those with indeterminateBRCAorigin had a median PFS of 7.1 months.BRCA1mutation was associated with a median PFS of 12.8 months andBRCA2with a median PFS of 11.2 months.

The most commonly reported treatment emergent adverse events AEs, any grade, were nausea (78%), asthenia/fatigue (78%), vomiting (49%), anemia (48%), dysgeusia (40%), elevated AST/ALT (39%), decreased appetite (39%), abdominal pain (38%), constipation (35%), diarrhea (34%), thrombocytopenia (25%), elevated creatinine (23%), dyspnea (23%), and urinary tract infection (20%). The most common grade 3/4 AEs were anemia (29%), asthenia/fatigue (10%), and elevated liver enzymes (10%).

AEs led to dose reductions in 49% of patients and to treatment discontinuation in 16%.