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

Danielle Bucco
Published: Saturday, Feb 10, 2018

Rebecca C. Arend, MD
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.

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.

OncLive: What is the rationale behind novel combinations with immunotherapy in 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.

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.

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

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.

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