HONOLULU – Adding trabectedin to pegylated liposomal doxorubicin (PLD) significantly prolongs overall and progression-free survival in BRCA1/2-mutated patients with advanced-relapsed epithelial ovarian cancer after two prior lines of platinum-based therapy, according to prespecified subgroup analyses of a randomized, open-label, phase 3 trial.
Patients with a platinum-free interval (PFI) of 6-12 months also experienced significantly improved progression-free survival (PFS), and those with both a BRCA mutation and PFI of 6-12 months experienced significantly improved overall survival (OS) and PFS with combined trabectedin and PLD vs. PLD alone, Bradley J. Monk, MD, reported at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer.
Of 576 patients enrolled in the289 received the combination regimen, and 287 received PLD alone. The study completed enrollment but was discontinued on January 18, 2018, after an interim analysis showed the futility threshold for OS and observed toxicity in the combination therapy group was exceeded.
OS was 21.5 and 22.2 months (hazard ratio = 1.13) in the combination and monotherapy groups, respectively. However, the subgroups analysis of patients with a germline BRCA1/2 mutation showed a median OS of 34.2 months with combination therapy and 20.9 months with PLD monotherapy, for a median survival benefit with combination therapy of 13.3 months (HR = 0.54), said, professor and director of the division of gynecologic oncology at Creighton University School of Medicine, St. Joseph’s Hospital and Medical Center, Phoenix, Ariz.
A subgroup of 60 patients with both a BRCA mutation and a PFI of 6-12 months had even greater improvement in OS with combination therapy when compared with PLD monotherapy (31.5 vs. 14.9 months; HR = 0.37). An effect on PFS was also detected in this subgroup (10.1 vs. 6.1 months; HR = 0.48), he said.
No difference in PFS was found in the overall unselected study population, Dr. Monk said, but among all patients with 6-12-month PFI alone, combination therapy led to significantly longer PFS than with monotherapy (7.5 vs. 5.5 months; HR = 0.72, P = .0388) and a positive trend in OS for the combination group (24.8 vs. 17.4 months; HR = 0.69; P = .565).
“I get it – this suffers from multiple comparisons, and this [analysis] in particular was ad hoc,” he said.
Still, given historical findings with respect to trabectedin in combination with PLD, the findings are provocative, he said.
Trabectedin is “a complicated anticancer cytotoxic medication”by the Food and Drug Administration in 2015 based on findings of treatment benefit in liposarcoma and leiomyosarcoma (including uterine leiomyosarcoma), he explained.
The agent has also been studied widely in other tumors, including in ovarian cancer. In the
That trial, which met its primary endpoint of an overall PFS benefit with trabectedin and generated the hypothesis that the agent might have particular benefit in BRCA-mutated patients, led to regulatory approval of trabectedin in Europe and elsewhere as an option for treatment in patients with partially platinum-sensitive recurrences – but not in the United States, he said.
Since OVA-301 did not lead to FDA approval, he and his colleagues designed the current study to look more closely at trabectedin with and without PLD, using the same dosing regimens as in OVA-301, but in the third-line setting and using OS as the primary endpoint.
Based on the intriguing OVA-301 findings in BRCA-mutated patients, the BRCA1/2-mutated subgroup analysis in thewas prespecified, he noted.
Study participants were women with advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who responded to two prior lines of platinum-based therapy and who were at least 6 months platinum-free. They were randomly assigned 1:1 to trabectedin plus PLD or PLD alone. Dosing in the combination arm was 1.1 mg/m2 of intravenous trabectedin over 3 hours and 30 mg/m2 of IV PLD given over 90 minutes every 3 weeks, and in the monotherapy arm PLD was given at a dose of 50 mg/m2 IV over 90 minutes every 4 weeks.
The groups were well balanced with respect to age, race, and performance status, and each included “a smattering of histological subtypes,” he said.
Of the 576 enrolled, 155 were BRCA1 or BRCA2-positive, with about two-thirds carrying a BRCA1 mutation.
Very few were exposed to bevacizumab or poly(ADP ribose) polymerase (PARP) inhibitors, as the study was initiated before those were developed.
Adverse events (AEs) of all grades occurred at similar rates in the two arms and occurred in most patients. Most were drug-related, but grade 3-4 AE rates were higher in the combination arm (79% vs. 54%). Drug-related AEs leading to treatment discontinuation occurred in 32.5% and 16% of the combination and monotherapy arm patients, respectively, Dr. Monk said.
“Most of those treatment-related AEs were cytopenia and/or transaminitis. There were also almost twice as many deaths in the combination arm: 3.5% vs. 1.6%,” he said, adding that the deaths were thought to be related to tumor progression rather than to the drugs.
Although the addition of trabectedin to PLD did not prolong OS, compared with PLD alone in unselected patients with advanced, third-line, recurrent ovarian cancer, the combination does appear to benefit patients with germline BRCA mutations, a 6-12 month platinum-free interval, or both, he said, concluding that “the results of this phase 3 subanalysis are consistent with the previous observations in OVA-301 that trabectedin alone or with PLD displays selective antitumor activity in this BRCA subgroup.
“It adds more toxicity, but no new safety signals were identified,” he added.
Asked during a panel discussion if he thinks these results mark “then end of the road” for trabectedin, Dr. Monk said he does not.
“I don’t think we should be penalized because we enrolled all those non-BRCA patients. When you look at the BRCA cohort I think there is an opportunity to get this to our patients,” he said, noting that “the major challenge” is that those patients had not been given a PARP inhibitor. “So I think that there might be an opportunity for licensing, but the confirmatory trial would have to [look at whether] the drug still works after failure of a PARP.”
The EJanssen Research & Development. Dr. Monk reported financial relationships (consulting, honoraria/reimbursement, and/or speaker’s bureau participation) with Janssen/Johnson & Johnson and more than 20 other pharmaceutical companies.
SOURCE: Monk B et al., SGO 2019: .