Studies Seek to Expand on PARP Inhibitor Success in Ovarian Cancer

Susana M. Campos, MD

With 3 PARP inhibitors available for patients with recurrent ovarian cancer and in the maintenance setting, Susana Campos, MD, MPH, said that ongoing clinical trials will answer questions about where the future management of the disease is headed.

Such queries could be addressed in 2019, following the practice-changing data of the phase III SOLO-1 trial that were presented at the 2018 ESMO Congress. In the study, the PARP inhibitor olaparib (Lynparza) reduced the risk of disease progression or death by 70% in patients with BRCA-mutant advanced ovarian cancer who were in complete or partial response to platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41; P <.0001) versus placebo following chemotherapy.

The FDA approved olaparib in December 2018 as a maintenance therapy for patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to frontline platinum-based chemotherapy.

“The SOLO-1 trial really opened our eyes that there is a tomorrow for patients with ovarian cancer,” said Campos, an assistant professor of medicine, Harvard Medical School, and Dana-Farber Cancer Institute.

Following the single-agent PARP inhibition activity, clinical trials are ongoing to determine the efficacy with them in combination with antiangiogenic agents, immunotherapy, and chemotherapy, Campos explained. One such trial, ATHENA (NCT03522246), is evaluating the combination of rucaparib (Rubraca) and nivolumab (Opdivo) as maintenance therapy following first-line platinum-based chemotherapy.

OncLive: Could you highlight the key takeaways from your presentation on PARP inhibitors?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Ovarian Cancer, Campos highlighted the success with PARP inhibitors in the relapsed and maintenance ovarian cancer settings.Campos: We talked about PARP inhibitors and how they have infiltrated the world of ovarian cancer, and in many ways how they have changed the course of ovarian cancer. I spoke a bit about what some of the PARP inhibitors are in the recurrent setting as single agents—where it all started.

Then, I moved onto maintenance therapy, which is an extremely important area. We do a great job of treating women with ovarian cancer and putting them into remission, but the disease in of itself doesn’t stay in remission. Some of the studies, NOVA, SOLO-2, Study 19, and ARIEL3 showed us that we can keep individuals in remission a little longer.

The SOLO-1 trial had practice-changing findings. Could you highlight that study and the data?

We also spoke about interesting data about the SOLO-1 trial, which was a highlight of the 2018 ESMO Congress. Then, we talked about if PARP inhibitors work as single agents, what if we were to combine them with other agents, such as antiangiogenic agents? In terms of immunotherapy, my colleague [Panagiotis A. Konstantinopoulos, MD] also spoke on PARP inhibitors and immunotherapy. Therefore, in my lecture, we talked about where [PARP inhibition] started, where it is today, and where we think we're going tomorrow [with them].The SOLO-1 trial was specifically in BRCA-mutation carriers, so patients in the upfront setting, after they finished chemotherapy and if they were in complete remission, were subsequently randomized to an intervention, which in this case was olaparib or placebo, and they were followed.

What are the differences between the 3 available PARP inhibitors?

They were on treatment for about 2 years, and in a landmark analysis of about 3 years, it was striking because of the patients who were randomized to olaparib, at least 60% were progression free at that time as opposed to about 24% [who had placebo]. This is statistically significant. Where this pans out in the future, [the question is], does it improve OS? It is too early to tell. These are not mature results, but at least at first blush, these are incredibly exciting data. Everyone in the room understands and gets a chill when they actually see these data.We know, in essence, that they are pretty similar. There are olaparib, niraparib (Zejula), and rucaparib. There are going to be more at the end of the day. We know that they have some common side effects; for example, there is anemia, thrombocytopenia, and leukopenia. We know that there are gastrointestinal toxicities, but some of them have some unique toxicities.

For example, niraparib can have a little bit more thrombocytopenia, but you can circumvent that by lowering the dose. [Thrombocytopenia may occur] if a patient weighs less than 77 kilograms and has a platelet count of less than 150,000. There are some unique toxicities; some have some more photosensitivity, such as rucaparib, and some [lead to an] increase in liver function tests, though that’s not a clinically significant finding. It doesn’t impair clinical course, but as a whole, they pretty much have the same side effect profiles overall. There is the potential for myelodysplastic syndrome with all of them.

What ongoing trials in this space are you excited about?

There is also the issue of hypertensive crisis with niraparib, so you have to be knowledgeable about these toxicities. In my opinion, this is no different than when we learned to use many different drugs. We have to often learn how to finesse the drug, understand what the patient can tolerate, and acclimate to the FDA dosage if it’s appropriate in a given patient. It takes a little practice.There is PRIMA, which will not only restrict the eligibility criteria to that of BRCA mutation carriers but also to homologous repair deficiency (HRD)—positive patients. The PAOLA data are going to be very exciting. We talk a lot about bevacizumab (Avastin), and we talk a lot about PARP inhibitors; however, the combination is a good rationale as to why using antiangiogenics with a PARP inhibitor may be very fruitful.

Then, there are studies that will eventually have results: ICON 9, the GY-004, and GY-005. [There are many studies] that really will show where the future is going. I also think some of the trials my colleague talked about [are interesting], such as JAVELIN Ovarian PARP 100, the FIRST trial, and I’m particularly fond of the ATHENA trial because it engages patients after the completion of standard of care.

Why might some of these PARP inhibitor combinations be effective? What is the rationale for them?

What do we know about veliparib?

When you reflect on the 2018 advances, what have we learned about the ovarian cancer space? Where will we be one year from now?

All of those will tell us, “Can you mix the immunotherapy activity with that of a PARP inhibitor, and what are the results of that?” It certainly gives women with ovarian cancer so much more to look forward to and to hang their hat on.At this point in time, it’s all experimental, but in essence when you use antiangiogenics you create a hypoxic state, which in essence may create a BRCA-ness and that may increase the possibility of HRD and then increase the sensitivity to PARP inhibitors. Immunotherapy is very interesting; when you give a DNA-damaging agent you create more neoantigens, you activate the STING pathway, and at that time, you may get a nice robust immune response to the use of the PARP inhibitors with ovarian cancer. These are all hypotheses, and time will tell [if they are accurate]. Sometimes when things look good on paper, we have to clinically play it out.We know a little about this. It is part of an upfront study looking at a standard of care, standard of care plus veliparib followed by placebo maintenance versus veliparib plus chemotherapy followed by veliparib maintenance. Therefore, we will understand a little bit about what brings to the table as a result of that particular trial.SOLO-1 is probably the most exciting data because if you can make an impact on women with ovarian cancer very early on, you may change the course of their life at this point in time. It answers some questions and establishes other questions that have to be answered. If a patient receives a PARP inhibitor upfront as maintenance, can they still respond to a PARP inhibitor later on? Could they respond to a combination? What are the mechanisms of resistance to patients who have been on PARP inhibitors?