PARP Combos With Bevacizumab, Immunotherapy in Development for Ovarian Cancer Treatment

Rebecca C. Arend, MD

The way forward for the treatment of patients with ovarian cancer will be with novel combination regimens, according to Rebecca C. Arend, MD.

For example, bevacizumab (Avastin) is an antiangiogenesis agent that is being combined with many different regimens to increase the overall outcomes for patients. In the phase I stage of the phase I/II ENGOT-OV24/AVANOVA1 study of the combination of niraparib (Zejula) plus bevacizumab, the objective response rate was 45%.

The primary endpoint of the phase II portion of the study is progression-free survival with a secondary endpoint of disease control rate (NCT02354131). Patients will be randomized to niraparib monotherapy until progression or niraparib in combination with bevacizumab.

OncLive: What is the rationale behind novel combinations with immunotherapy in ovarian cancer?

In an interview with OncLive during the 2018 Society of Gynecologic Oncology Winter Annual Meeting, Arend, an assistant professor, University of Alabama (UAB) School of Medicine, UAB Department of Obstetrics and Gynecology, UAB Comprehensive Cancer Center, discussed novel combinations being investigated for the treatment of patients with ovarian cancer.Arend: Firstly, patients who respond to single-agent immunotherapy are going to have a higher percentage of tumor infiltrating lymphocytes (TILs). However, a patient cannot just have TILs, they need to have the right antibodies, such as CD137- or CD103-directed antibodies.

Those T cells can become exhausted. If they become exhausted, that patient is not going to respond to immunotherapy. In trials, 15% of patients with ovarian cancer will respond to single-agent immunotherapy. We want to know if we can prime the immune system to increase the live T cells that are able to fight off the cancer and then add immunotherapy.

Another way to do combination therapy is on the back end. Cells become resistant to the immunotherapy so they upregulate other things. For instance, if you give a PD-L1 inhibitor, you may have the CTLA-4 pathway, the LAG3 pathway, or others that are all different checkpoint pathways. To compensate, it targets 2 things at the same time.

The other idea is that we are also starting to use antiangiogenic agents, PARP inhibitors, and chemotherapy. The real proof is going to be in the sequencing of them and the biomarkers. We need to figure out who needs what regimen, who can receive single agents, and how long a patient can receive a single agent before they need an immune-modulator for the immunotherapy to continue working. Perhaps for other patients, they will need an immune modulator first and then immunotherapy. There will be other patients for whom when given immunotherapy, they will have T-cell exhaustion and are going to need something to help them overcome that.

What are some combinations at the forefront in terms of efficacy?

There are many different ways combinations can happen. I am hopeful that we can give them to everyone. We are not there yet, in terms of saying which women can receive a certain sequence versus another. We have many different trials with different combinations, but our hope is that we can be more rational about who we give certain combinations to. In the beginning, we have to give the same thing to a large number of patients to figure out what works best.At the forefront, there are 3 players in ovarian cancer. The first one was bevacizumab or VEGF inhibition or angiogenesis agents. It does not necessarily have to be bevacizumab, but I talked about other potential angiogeneic-targeting agents that work with immunotherapy. We also have cediranib and poziotinib and many other anti-angiogeneic molecules. That is one huge category that we first used in combination with chemotherapy or as a single agent.

More recently, there are 3 PARP inhibitors approved. There is a lot of talk about the fact that many women will respond to PARP inhibitors, but there are some who will not. That is a very promising combination. There is going to be a subset of patients who will need both, but possibly not at the same time. There may be patients who benefit from receiving bevacizumab first followed by a PARP inhibitor. There may be other patients who benefit from getting a PARP inhibitor first, followed by bevacizumab.

Checkpoint inhibitors are the furthest along. Bevacizumab, among other antiangiogenic agents, and PARP inhibitors have promise in combination with checkpoint inhibitors.

Can you discuss some of the data around PARP inhibitors and bevacizumab?

We are also combining different immunotherapy agents. That can be stratified into 2 categories. The first is to use different checkpoint inhibitors, such as a PD-L1 or CTLA-4. Beyond that is using cytokine therapy or vaccines in combination with checkpoint inhibitors. Those ideas are revving up the immune system and then stopping it from the negative feedback that it ordinarily would undergo. There are a lot of layers of combination therapies, but those are the big categories.There have been trials that have looked at niraparib and bevacizumab in the platinum-resistant setting. There was a poster presented at the 2017 ESMO Congress that showed some promising data. That trial is still ongoing so we do not have the final data. There are people who use that combination off-label, but it is currently only available in trials. However, niraparib and bevacizumab are both FDA-approved drugs.

I would advocate for someone who is going to try those drugs to do it on a trial so that we can organize our data and outcomes for those combinations. There are certainly trials with some encouraging results, but nothing final yet.

There are several trials that are looking at the combination of immunotherapy and VEGF inhibitors. Due to the fact that bevacizumab will [likely] become FDA approved in the upfront setting, a lot of the trials that are now being designed include bevacizumab as maintenance, immunotherapy as maintenance, and a combination of immunotherapy and bevacizumab.

In the platinum-resistant setting, we have several trials that are combining bevacizumab or different antiangiogenic agents with immunotherapy as treatment.

Mirza MR, Wang J, Mau-Sorensen M, et al. A phase 1 study to evaluate the safety and tolerability of bevacizumab-niraparib combination therapy and determine the recommended phase 2 dose (RP2D) in women with platinum-sensitive epithelial ovarian cancer (ENGOT-OV24/AVANOVA1). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 953P.

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