David O’Malley, MD, discusses clinical trials in ovarian cancer and others under investigation.
David O'Malley, MD
Ongoing clinical trials are looking at a multitude of novel approaches in ovarian cancer, including immunotherapy, explained David O’Malley, MD, who emphasized the need for more studies to determine patient selection for each treatment.
“Clinical trials in ovarian cancer are the absolute highest priority, especially in those frontline ovarian cancer patients,” said O’Malley. “We need to look for opportunities to get as many of our patients onto clinical trials to get these important questions answered as soon as possible. Encourage every practitioner out there to open at least 1 frontline trial that you can enroll your patients on.”
One phase III trial, PAOLA-1, showed encouraging data with the combination of PARP and VEGF inhibition. Results showed that frontline maintenance therapy with olaparib (Lynparza) plus bevacizumab (Avastin) led to a median progression-free survival of 22.1 months versus 16.6 months with bevacizumab alone in patients with newly diagnosed, advanced ovarian cancer following prior treatment with platinum-based chemotherapy and bevacizumab (HR, 0.59; 95% CI, 0.49-0.72; P <.0001).
Two ongoing phase III trials, ATHENA (NCT03522246) and DUO-O (NCT03737643), are evaluating immunotherapy combinations in this disease. ATHENA is evaluating rucaparib (Rubraca) plus nivolumab (Opdivo), rucaparib plus placebo, placebo plus nivolumab, and placebo alone in patients with newly diagnosed ovarian cancer who respond to initial treatment with platinum-based chemotherapy.
DUO-O is investigating durvalumab (Imfinzi) in combination with chemotherapy and bevacizumab. This will be followed by a maintenance triplet of durvalumab, bevacizumab, and olaparib or durvalumab/bevacizumab alone after primary debulking surgery or neoadjuvant chemotherapy in patients with newly diagnosed advanced ovarian cancer.
In an interview during the 2019 OncLive® State of the Science Summit™ on Ovarian Cancer, O’Malley, a professor in the Department of Obstetrics and Gynecology, and director of the Division of Gynecologic Oncology at The Ohio State University Comprehensive Cancer Center—James, discussed these clinical trials in ovarian cancer and others under investigation.
OncLive: What questions still remain in ovarian cancer treatment?
O’Malley: The biggest question is, “What group of patients are going to benefit the most [from each therapy]?” Clearly, BRCA1/2—mutant patients are going to benefit from PARP inhibitors. Two additional trials [with PARP inhibitors in ovarian cancer] were published in 2019—PRIMA and VELIA—that are going to significantly impact patients in the upfront setting.
The biggest question beyond the BRCA1/2-mutant patients is, “How do we define homologous recombination deficiency positivity?” Which test should we do? For patients who are biomarker negative, how much benefit are they getting [from PARP inhibitors]? Should those patients be using combination therapy? However, when we look at PAOLA-1, in a subanalysis, the biomarker-negative patients did not show benefit of the combination. There are still a lot of questions regarding the optimal patient to receive PARP inhibitor as first-line maintenance.
Pending the FDA approvals of these regimens, is there rationale to who will receive which one first?
That is what we're trying to define. We're trying to find what patient group [will benefit the most]. Right now, olaparib was approved in BRCA1/2-mutant patients—both somatic and germline mutations. With regards to niraparib, if the approval is an all-comers population, what patient do you choose [to give niraparib] to over bevacizumab?
[Reflecting on] PAOLA-1, should we be using the combination [of olaparib and bevacizumab]? Then, once [the role of] veliparib is established, the next question is, "Should you start a PARP inhibitor with chemotherapy, which is the only agent that we can consistently combine with chemotherapy?" That question is particularly important as we look at patients with BRCA1/2 mutations.
How do the safety profiles of these regimens compare?
The PARP inhibitors are more similar than different with regards to toxicity. Veliparib, which is not yet on the market, seems to be better tolerated regarding hematologic toxicity. As we look at veliparib-treated patients, all of them have issues with gastrointestinal adverse events (AEs) such as nausea, and then constitutional AEs, such as fatigue.
Niraparib seems to be more challenging with regards to hematologic toxicity, specifically thrombocytopenia, but with their new “weights and plates” guidance seems to be improved. There are also some subtle differences with the other agents in regard to the dosing of olaparib in regard to [alanine aminotransferase levels] on rucaparib.
What is the current state of immunotherapy in ovarian cancer?
That is what we're studying right now. As we look at these agents, who do we think will benefit from them? The frontline setting and the immune environment is probably the best opportunity [to look at immunotherapy]. With regards to what [immunotherapy] agents to combine, should we combine them with PARP inhibitors? Do we need them combined with endovascular therapy? Or how about we combine them with both approaches, thereby creating a 3-drug regimen?
The challenge of that is that we haven't seen as much overlapping toxicities that are necessary to sort out. What patients will benefit from 1 drug, and what patients will need to receive all of those drugs at once? Our results with single-agent immunotherapy at this point, unfortunately, have not panned out. However, we are much more optimistic that one of the many clinical trials in the upfront setting will be positive, and we'll be able to better identify those patients who are going to benefit.
What ongoing studies are looking at immunotherapy in ovarian cancer?
There are multiple ongoing studies. In the United States right now, one of the largest trials is ATHENA—a 4-arm, placebo-controlled trial that examines rucaparib and nivolumab. Patients receive either single-agent rucaparib, rucaparib plus nivolumab, nivolumab, or placebo. This is in the maintenance setting. In those scenarios, [the trial is] trying to identify the patients who are going to benefit the most and sort out the relative contribution of each one of those agents.
Another large trial is DUO-O, which is a large, 3-arm, randomized phase III trial [of durvalumab combined with chemotherapy and bevacizumab, followed by maintenance durvalumab, bevacizumab and olaparib in advanced ovarian cancer].
With 3 frontline maintenance studies, is there a way to give these regimens sequentially?
The question of sequence versus combination will not be answered. We think the best option is using [the drugs in] combination. We are trying to overcome some of the immunogenicity or increase the immunogenicity of the tumors so that the checkpoint inhibitors will have greater benefit, as well as make them more BRCA-like by the using the anti-VEGF therapy. We think our best bet is to use them in combination, but the question of sequencing is not being asked in the current clinical trials.
Ray-Coquard IL, Pautier P, Pignata S, et al. Phase III PAOLA-1/ENGOT-ov25 trial: olaparib plus bevacizumab (bev) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCh) plus bev. Ann Oncol. 2019;30(suppl 5). doi: 10.1093/annonc/mdz394.053.