Robert L. Coleman
BARCELONA, Spain — The addition of veliparib to frontline chemotherapy followed by maintenance with veliparib monotherapy significantly prolonged PFS among women with newly diagnosed, high-grade serous ovarian carcinoma, according to results of the randomized phase 3 VELIA/GOG-3005 trial presented at European Society for Medical Oncology Congress.
Researchers observed the benefit of veliparib (ABT-888, AbbVie) — a poly (ADP-ribose) polymerase (PARP) inhibitor — in the entire cohort regardless of BRCA mutation or homologous recombination deficiency status.
These data support veliparib administered during chemotherapy and continued as maintenance as a new standard of care for women with newly diagnosed ovarian cancer, Robert L. Coleman, MD, professor of gynecologic oncology and reproductive medicine at The University of Texas MD Anderson Cancer Center, told HemOnc Today.
Prior studies have yielded robust data to support the effectiveness of PARP inhibitors for women with ovarian cancer. However, those studies predicate that response has been achieved during the initial treatment setting, Coleman said.
“That’s important because we feel it might be a biomarker for a class of patients who might benefit from these drugs,” Coleman said in an interview. “But when we sit down with a patient who is newly diagnosed and we plan our operative and chemotherapy strategy, we don’t have the luxury of knowing what is going to happen in the future. I want to be able to offer them the best therapy possible, not knowing whether that person is going to respond to treatment. We have two assets that have been studied in that way — bevacizumab [Avastin, Genentech] and now veliparib.”
There has been interest in combining PARP inhibitors with cytotoxic chemotherapy for ovarian cancer treatment, but those efforts have been limited by unacceptable hematologic toxicity that often requires substantial dose reductions, Coleman said.
Veliparib has demonstrated combination and single-agent activity for women with recurrent germline BRCA1- or BRCA2-positive ovarian cancer. It has been combined successfully with the standard doses of several cytotoxic agents, including carboplatin and paclitaxel.
Coleman and colleagues conducted the international, placebo-controlled VELIA/GOG-3005 trial to assess the efficacy and safety of adding veliparib to first-line induction chemotherapy with carboplatin and paclitaxel, followed by veliparib maintenance monotherapy, for women with previously untreated stage III or stage IV high-grade serous epithelial ovarian cancer.
Researchers enrolled 1,140 women with ECOG performance status of 0 to 2 and no central nervous system metastases. About one-quarter (26%) had BRCA mutations and more than half (55%) had homologous recombination deficiency.
Investigators randomly assigned patients 1:1:1 to one of three regimens: chemotherapy plus placebo followed by placebo maintenance (veliparib throughout; n = 375); chemotherapy plus veliparib followed by placebo maintenance (veliparib combination-only; n = 383); or chemotherapy plus veliparib followed by veliparib maintenance (control; n = 382).
Each regimen consisted of 36 cycles.
Chemotherapy — administered in six 21-day cycles — included carboplatin area under the curve 6 every 3 weeks, plus paclitaxel dosed at either 80 mg/m2 weekly or 175 mg/m2 every 3 weeks.
Veliparib was dosed at 150 mg twice daily when used with chemotherapy, and at 400 mg twice daily during the 30-cycle maintenance phase.
Relative dose intensities of carboplatin/paclitaxel were comparable between treatment groups.
Investigators stratified randomization by disease stage, region, primary vs. interval cytoreduction, residual disease after primary surgery, chemotherapy regimen and germline BRCA status.
The difference in investigator-assessed PFS between the veliparib-throughout group and control group served as the primary endpoint. Secondary endpoints included OS in the veliparib-throughout group vs. the control group, PFS and OS in the veliparib combination-only group vs. control; and disease-related symptoms in all three cohorts.
The primary endpoint analysis showed women in the veliparib-throughout group achieved significantly longer median PFS than women in the control group.
This trend appeared consistent among women with BRCA mutations (34.7 months vs. 22 months; HR = 0.44; 95% CI, 0.28-0.68), those with homologous recombination deficiency (median, 31.9 months vs. 20.5 months; HR = 0.57; 95% CI, 0.43-0.76) and all patients in the intent-to-treat population (23.5 months vs. 17.3 months; HR = 0.68; 95% CI, 0.56-0.83),
The benefit with the veliparib-throughout regimen appeared consistent in all key subgroups, Coleman said.
Administration of veliparib with chemotherapy but not during maintenance appeared associated with increased rates of response; however, researchers observed no PFS improvement in this group compared with the control regimen.
OS data are still immature, Coleman said.
“The tricky part about interpreting OS is that PARP inhibitors are already available so, for the women who didn’t get it in our study during chemotherapy or as maintenance, there’s a very good chance they’ll get it as part of the standard of care in the recurrent setting,” Coleman told HemOnc Today. “The OS data will be informative but it’s a very high bar to hit when you have patients living a long time.”
The toxicities observed among veliparib-treated women appeared consistent with the agent’s known safety profile, Coleman said.
Incidence of grade 3 or grade 4 adverse events during carboplatin/paclitaxel treatment were comparable among women assigned veliparib or placebo with the exception of thrombocytopenia, which occurred more frequently among veliparib-treated women (27% vs. 8%).
In the maintenance phase, a higher percentage of women assigned veliparib than placebo experienced any grade 3 or grade 4 adverse event (45% vs. 32%). However, rates of serious adverse events were comparable between treatment groups (17% vs. 19%).
The results of this trial further validate the role of PARP inhibitors in ovarian cancer treatment and “offer a new therapeutic asset” that can be initiated at the beginning of adjuvant chemotherapy, Coleman said.
However, the transition of these agents to an earlier treatment line will pose a new challenge.
“PARP inhibitors are broadly approved in the recurrent setting and as primary maintenance. Now we have a new crop of patients who have had a PARP inhibitor earlier,” Coleman told HemOnc Today. “We are already starting to deal with the issue of how we interpret the ‘old’ studies given the fact none of those patients had a PARP inhibitor before. We’ll have to start stratifying for prior exposure.
“One thing we know is that, if someone got a PARP inhibitor and they progressed on it, they probably won’t get much benefit from retreatment with a single agent,” he added. “However, that doesn’t necessarily mean we couldn’t come up with a combination that would be effective.”
Additional insights are needed to determine whether a PARP inhibitor could be active for patients with wild-type disease, a setting in which a PARP effect wouldn’t be expected.
“Is there a way to give something with a PARP inhibitor — such as an immune checkpoint inhibitor, angiogenesis inhibitor or another DNA-damaging pathway inhibitor — that would become active in that setting and turn a patient with wild-type disease into somebody who might respond?” Coleman said.
Efforts also must continue to improve outcomes among patients who already respond to this class of agents, he said.
“There’s definitely room for improvement,” Coleman said. “Even though these are great drugs and we’re seeing groundbreaking changes, we can always do better. The question is, how can we do that?” – by Mark Leiser
Reference: Coleman RL, et al. Abstract LBA3. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
Disclosures: AbbVie funded this study. Coleman reports consultant/advisory roles with, research grants/funding from, or travel accommodations or expenses from Abbott, AbbVie/Stemcentrx, Array BioPharma, AstraZeneca/MedImmune, Clovis Oncology, Esperance, Genentech/Roche, GamaMabs Pharma, Genmab, Gynecologic Oncology Group, Johnson & Johnson, Merck, National Comprehensive Cancer Network, Oncolytics, OncoMed, Research to Practice, Sotio, Tesaro and Vaniam Group. Please see the abstract for all other authors’ relevant financial disclosures.