An updated analysis of the phase III VELIA/GOG-3005 trial, presented during the 2020 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer Webinar Series,1 suggested synergy between the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and platinum chemotherapy in the front-line setting prior to maintenance therapy for women with advanced ovarian cancer. However, questions about the clinical relevance of the combination remain.
Kathleen N. Moore, MD
Discussant of the abstract, Kathleen N. Moore, MD, of the Stephenson Cancer Center, Oklahoma City, asked whether the increased toxicity that comes with adding veliparib to chemotherapy is worth it in all comers, for example, if longer progression-free survival cannot be demonstrated.2 The study authors, on the other hand, still see a role for veliparib in the front-line setting.
“The availability of agents that can be combined at full doses with chemotherapy is quite limited,” said Robert L. Coleman, MD, of The University of Texas MD Anderson Cancer Center. “Because of the specific drug characteristics of veliparib, it has been shown it can be combined with chemotherapy, making it an attractive option with front-line chemotherapy that we can use for ovarian cancer.”
As Dr. Coleman reported at the European Society for Medical Oncology (ESMO) 2019 Congress,3 veliparib added to chemotherapy and continued as maintenance significantly extended progression-free survival in all patient cohorts with newly diagnosed high-grade serous ovarian carcinoma, regardless of biomarker, choice of surgery, or paclitaxel regimen. Reduction of hazard for recurrence or disease progression was 56% in patients with BRCA mutations, 43% in patients with homologous recombination deficiency (HRD), and 32% in the intention-to-treat population. However, when given during chemotherapy cycles alone, said Dr. Coleman, veliparib did not demonstrate an increase in progression-free survival, although a numerically higher objective response rate was observed for both veliparib-containing arms. The data were subsequently published in The New England Journal of Medicine.4
During the SGO webinar, Dr. Coleman said investigators are still “drilling down deeper into the data” to identify the benefit of giving veliparib during chemotherapy. “Ultimately, we feel veliparib can be safely administered, and the adverse events are consistent, both during chemotherapy and during the maintenance phase, with what has previously been seen,” he said. “We think this agent should be considered a new treatment option for patients with newly diagnosed, advanced-stage ovarian cancer.”
‘Extended Window of Benefit’ for PARP Inhibition?
Study coauthor David M. O’Malley, MD, Professor of Obstetrics and Gynecology at The Ohio State University College of Medicine, focused on the combination or induction phase of the study, which was the first six cycles of treatment with carboplatin and paclitaxel.5 Two of the treatment arms received veliparib in combination with standard carboplatin and paclitaxel (either weekly or every 3 weeks), whereas the control arm received carboplatin and paclitaxel alone.
“Our findings suggest PARP inhibitor maintenance may be beneficial for a larger population of patients than has previously been studied.”— David M. O’Malley, MD
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As Dr. O’Malley reported, the progression-free survival benefit of veliparib combined with carboplatin and paclitaxel and continued as maintenance was seen across each of the primary endpoint patient populations (hazard ratio [HR] = 0.68; P < .001). As a secondary endpoint, veliparib combined with chemotherapy and stopped after the combination phase will be evaluated later, according to the prespecified testing hierarchy. However, the informal analysis failed to show a progression-free survival benefit with this arm compared with chemotherapy alone.
Because the number of early progression-free survival events during chemotherapy was too small to allow meaningful comparison between study arms, Dr. O’Malley and colleagues evaluated veliparib activity for the combination phase as assessed by radiographic response per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, or CA-125 response (defined as ≥ 90% reduction). Investigators assessed objective response rates from patients with measurable disease after primary surgery (n = 290, 25% of intention-to-treat population) and collected CA-125 levels at baseline and on day 1 of each treatment cycle during the combination phase. Both veliparib-containing arms were combined for analysis.
As Dr. O’Malley reported, analysis of radiographic and CA-125 responses showed veliparib may provide incremental antitumor activity when combined with front-line platinum chemotherapy prior to maintenance. During the first six cycles, the veliparib-containing arms yielded the following:
- Higher proportion of patients with objective responses and complete responses per RECIST, version 1.1
- Higher proportion of patients with at least a 90% reduction in CA-125 levels
- Higher CA-125 response prior to surgery in patients undergoing interval debulking surgery
- Increased CA-125 response in both HRD and non-HRD patient populations.
“Taken together,” said Dr. O’Malley, “these analyses suggest an extended window of benefit for PARP inhibition vs a maintenance-alone approach.”
Novel Study Design
Dr. O’Malley also highlighted VELIA’s unique design, which was “very different” from other PARP inhibitor trials. As he explained, VELIA enrolled a broad patient population in which all patients without disease progression could receive veliparib or placebo in the maintenance setting. The study also was designed to evaluate the addition of PARP therapy from the start of front-line treatment.
Under typical PARP inhibitor maintenance trial protocols, noted Dr. O’Malley, patients with stable disease at the end of chemotherapy are not eligible for maintenance; only responders are eligible. In VELIA, however, this population represented up to 28% of the control arm at the end of chemotherapy.
“Our findings suggest PARP inhibitor maintenance may be beneficial for a larger population of patients than has previously been studied,” Dr. O’Malley concluded.
DISCLOSURE: Dr. Coleman has served as a consultant or advisor to Clovis Oncology, Genentech/Roche, Esperance, AstraZeneca/MedImmune, Genmab, GamaMabsPharma, Tesaro, OncoMed, Sotio, Oncolytics, and AbbVie; has received reimbursement for travel, accommodations, and expenses from Merck, AstraZeneca/MedImmune, Array Biopharma, Clovis Oncology, Roche/Genentech, Research to Practice, GOG-Partners, Sotio, and Vaniam Group; and has received research funding from AstraZeneca/MedImmune, Esperance, OncoMed, Array, Clovis Oncology, Johnson & Johnson, Merck, Roche/Genentech, Abbott/AbbVie, and GOG Foundation. Dr. OMalley has received honoraria and/or institutional research support from AstraZeneca, Clovis, Tesaro, Immunogen, Janssen/J&J, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, Eisai, Agenus, GSK, Merck, GOG Foundation, VentiRx, Array Biopharma, EMD Serono, Ergomed, Ajinomoto, Ludwig Cancer Research, Stemcentrx, Cerulean Pharma, Bristol Myers Squibb, Serono, Tracon Pharmaceuticals, Yale University, New Mexico Cancer Care Alliance, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, PRA International, Tarveda, Ambry, and Myriad Genetics.
REFERENCES
1. Coleman RL: Integration of veliparib with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin. 2020 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer. Abstract 36. Presented March 29, 2020.
3. Coleman RL, Fleming GF, Brady MF, et al: VELIA/GOG-3005: Integration of veliparib with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin. ESMO 2019 Congress. Abstract LBA3. Presented September 28, 2019.
4. Coleman RL, Fleming GF, Brady MF, et al: Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med 38:2403-2415, 2019.
5. O’Malley DM, Bookman MA, Moore KN, et al: Anti-tumor activity of veliparib during combination phase with chemotherapy in VELIA study. 2020 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer. Abstract LBA9. Presented April 30, 2020.
