Therapy with poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, provided sustained benefit beyond the end of initial treatment for patients with newly diagnosed advanced ovarian cancers expressing the BRCA mutation (Abstract 5170). The Phase III SOLO1 trial of olaparib maintenance therapy compared with placebo reported long remissions and "potential cures" at ESMO Congress 2022.
"Sixty-seven percent of women were alive 7 years later," said lead author Paul DiSilvestro, MD, Professor of Obstetrics & Gynecology and Director of the Program of Women's Oncology at Women & Infants Hospital in Providence, RI. "The fact that two-thirds of these patients were still alive is a tremendous advancement in ovarian cancer care," he told Oncology Times.
Study Details
In the SOLO1 study, patients who responded to first-line platinum-based chemotherapy were randomized to treatment with maintenance olaparib or placebo for up to 2 years or until progression. A total of 260 patients had olaparib maintenance and 131 were treated with placebo. The median treatment duration was 24.6 months in the investigational arm of the study and 13.9 months in the control arm.
After 5 years follow-up, the median progression-free survival was 56.0 months with olaparib compared with 13.8 months for patients randomized to maintenance with placebo-a hazard ratio of 0.33. Forty-eight percent of patients remained free of disease after 5 years compared with 21 percent in the control arm of the study.
DiSilvestro reported at the meeting that the study brought early data indicating a "clinically meaningful" improvement in overall survival after 7 years follow-up. He said this was clinically relevant since most deaths from ovarian cancers occurred between 5 and 10 years after diagnosis.
Although crossover from placebo treatment to the investigational arm was permitted (and 44.3% of patients randomized to placebo eventually received a PARP inhibitor), nevertheless, after 7 years 45.3 percent of patients initially allocated to olaparib were alive and had still not received any subsequent treatment compared with 20.6 percent of patients originally randomized to the control arm remaining alive with no further intervention. Altogether 67.0 percent of patients treated with olaparib were alive 7 years later compared with 46.5 percent of those randomized initially to placebo.
The incidence of myelodysplastic syndrome and acute myeloid leukemia-both possible consequences of PARP inhibitor therapy-was low (around 1%)-and similar in both study arms.
The investigators concluded that 2 years of maintenance olaparib had provided "clinically meaningful improvement" in overall survival in comparison with placebo among patients with newly diagnosed advanced ovarian cancer expressing the BRCA mutation-with "no new safety signals" detected-supporting the use of maintenance olaparib to achieve long-term remission and potential cure.
DiSilvestro said recent progress in targeted therapy for ovarian cancer had been long awaited. By the turn of the century, little progress had been made.
"The only thing we had [then] was taxol and carboplatin combination chemotherapy-basically for all histologic types [and] all stages. It was the only way we treated ovarian cancer."
But about 10 years later, the first targeted agent for ovarian cancer had emerged-bevacizumab. "It showed progression-free survival benefit. In the end, it didn't show an overall survival benefit, but it led to practice change," DiSilvestro stated.
But the development of PARP inhibitors now seemed to have heralded a bigger change. "What we had realized from a biologic perspective was that ovarian cancers-and especially high-grade serous or endometrioid cancers (which are the majority of them)-demonstrated homologous recombination deficiency (HRD), which made them susceptible to DNA-damaging agents and, in this scenario, [to] the PARP inhibitors."
Early PARP-inhibitor data had shown "tremendous responses" in subsets of patients, DiSilvestro said. It became clear that patients-especially those with the BRCA-mutated marker-had significant benefits, he said. This eventually led to the SOLO1 study he reported at the ESMO Congress, which he noted brought the possibility of discovering whether people really could live longer by having 2 years of PARP-inhibitor maintenance.
SOLO1 did not discriminate between patients who tested positive or negative for the HRD marker, said DiSilvestro. The trial had focused solely on patients with BRCA mutations. But the findings were consistent with new data from the Phase III PAOLA-1 trial-also reported at the 2022 ESMO meeting-that had evaluated maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced ovarian cancer and found improved overall survival, especially in patients expressing the HRD marker.
DiSilvestro said a clear recommendation came out of the SOLO1 findings. "Patients who have advanced ovarian cancer and a BRCA mutation should be offered 2 years of maintenance olaparib at the end of their primary chemotherapy if they are in complete or partial response."
Although he wasn't ready to describe the treatment as a cure, he was optimistic. "If you look at the separation of the risk of somebody [dying] from their cancer-versus the risk to the average person who doesn't have cancer-that separation starts to merge at about 7 years. So, 7 years is a pretty good indicator of a potential for cure here."
Peter M. Goodwin is a contributing writer.