ASCO 2020-SURVIVAL BENEFIT WITH OLAPARIB MAINTENANCE IN BRCA+ OVARIAN CANCER

The SOLO2 trial found olaparib maintenance therapy may have clinically relevant effects on overall survival (OS) in women with platinum-sensitive relapsed ovarian cancer (PSROC) with BRCA1/2 mutations (Abstract 6002). Andrés Poveda, MD, of Initia Oncology, Hospital Quirónsalud and GEICO, Spain, presented survival and safety outcomes from the trial during the ASCO20 Virtual Scientific Program.

“Recurrent ovarian cancer remains incurable to the majority of women, and therefore, extending OS is of great importance,” said Discussant Susana Banerjee, MBBS, MA, PhD, FRCP, of The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, United Kingdom. “Improvements in progression-free survival, time to subsequent therapy, and response are clinically meaningful and important trial endpoints. The introduction of PARP inhibitors has really changed the landscape of ovarian cancer.”

“The introduction of PARP inhibitors has really changed the landscape of ovarian cancer.” – Dr. Andrés Poveda

Despite advances in the management of ovarian cancer, such as the advent of the PARP inhibitor olaparib, OS remains an elusive target of studies that seek to mitigate relapsing disease.

SOLO2 is an international, randomized phase III trial to examine olaparib maintenance treatment in women with PSROC with BRCA1/2 mutations who have received at least two lines of previous platinum-based chemotherapy. Patients were randomly assigned to olaparib 300 mg bid (196 patients) or placebo (99 patients) until disease progression. Time-dependent endpoints presented at the program included OS, time to first subsequent therapy, duration of treatment exposure, and safety and toxicity profiles.

OS failed to reach statistical significance (HR 0.74, p = 0.0537) but nonetheless represents a clinically meaningful outcome, Dr. Poveda said.

“[In] the final analysis on OS, the median OS improved by 12.9 months with maintenance olaparib over placebo,” he said. “This is an impressive finding, particularly considering that 38% of [patients receiving] placebo crossed over to receive PARP inhibitor therapy.”

Time to first subsequent therapy was significantly better among patients in the treatment arm than those in the control arm (median 27.4 vs. 7.2 months, HR 0.37; p < 0.0001). At 5 years, 42% of patients on olaparib were alive and had not received subsequent treatment, compared with 33% of patients on placebo.

Mean duration of treatment exposure was 29.1 versus 13.1 months for placebo. Tolerability was acceptable, with 22% of patients in the treatment arm remaining on maintenance olaparib after at least 5 years. Only a small number of treatment-emergent adverse effects, dose modifications, and treatment discontinuations occurred among patients receiving olaparib over long-term treatment. Toxicities of particular interest included the emergence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

“Perhaps the most important point here is the increased incidence in MDS and AML in both the olaparib arm at 8% and the placebo arm at 4%,” Dr. Banerjee said. “However of note, in the SOLO1 trial, where patients received first-line treatment for around 2 years, the incidence of MDS and AML was much lower—1% versus 0% in the placebo arm.”¹

Dr. Banerjee also emphasized that although OS in SOLO2 was clinically relevant, and it was “reassuring” to see that more than 1 in 5 patients remained on maintenance therapy for at least 5 years, unanswered questions about olaparib remain and should inform future studies.

“In the current era of first-line PARP inhibitor maintenance therapy, how relevant are these results and other recurrent trials, including the population of patients [who] are naive to PARP inhibitors?” she asked. “The reality is, there will remain a substantial proportion of women who would not have had PARP inhibitors in the first-line setting but then go on to relapse, and therefore this [question] is applicable.”

Dr. Banerjee also noted that there may be situations where a PARP inhibitor is reserved for recurrent disease in women with hormone receptor–proficient tumors.

“What about OS in patients without a BRCA mutation?” she asked. “We need to wait for [data from] NOVA and ARIEL3.”

— Emily A. Kuhl, PhD