Anil K. Sood, MD

Question 1.What is your view on the addition of bevacizumab to treatment regimens for BRCA-associated ovarian cancers?

Answer
There are several studies looking into this. In late 2019, the PAOLA-1 study (ClinicalTrials.gov Identifier: NCT02477644), published in The New England Journal of Medicine, studied olaparib plus bevacizumab as first-line maintenance. That was an interesting study.

The idea behind this came from an observation a few years ago where cediranib (an antiangiogenic drug) was combined with olaparib (a poly[ADP]-ribose polymerase [PARP] inhibitor) and there was better activity than with the antiangiogenic drug alone. Some investigators hypothesized that hypoxia may create abnormalities in DNA repair pathways that sensitized the tumor to a PARP inhibitor.

The PAOLA-1 trial met its primary endpoint; the issue was that a lot of the activity they saw was in patients with BRCA-positive or [homologous recombinant deficiency]-positive disease, and there was not a PARP inhibitor–alone arm. We know that PARP inhibitors are clearly active in this population. The question that arises is, would dual therapy have been better compared with PARP inhibition alone? We just don’t know.

It is an important study, but there is still a question that needs to be answered. Is it truly superior?

Another study out of [the American Society of Clinical Oncology 2020 (ASCO20) Virtual Scientific Program] looked at mirvetuximab [soravtansine] in combination with bevacizumab in patients with relapsed ovarian cancer.² In the relapse setting, we need additional options to be available because with the current therapies, the cancer comes back. It is not curative. Mirvetuximab is totally different than a PARP inhibitor. It targets [folate receptor alpha] on the cancer cell surface and it gets delivered in a more targeted manner. The combination biologically makes sense. In this study, they showed pretty robust response rates. It certainly seems like an exciting combination and worth developing further.

Question 2. Which data (and for which specific disease subtypes in ovarian cancer) that were presented during the ASCO20 Virtual Scientific Program might prompt changes to the use of/prompt increased uptake of PARP inhibitors, if any?

Answer
Although I am not sure it will change uptake, data from the VELIA study (ClinicalTrials.gov Identifier: NCT02470585) — which was also presented at [the European Society of Medical Oncology Congress] — was interesting because the study added a PARP inhibitor (veliparib) to chemotherapy.³ Previously, we had not been able to do that with other PARP inhibitors because of toxicity concerns.

The question then comes up whether you need to add a third drug along with chemotherapy and potentially take on more toxicities, or could you have done just as well giving chemotherapy and using PARP inhibitor maintenance? Could the drugs be given sequentially rather than jointly? These are open questions that require further study.

Question 3. Do you think it’s possible that the combination of PARP inhibitors with programmed death-1/programmed death ligand-1 (PD-1/PD-L1) blockade in the frontline setting could ever take the place of chemotherapy? Why or why not?

Answer
That is a great question without an answer. We at the University of Texas MD Anderson are conducting a study for patients who have a BRCA 1/2 mutation who are getting a PARP inhibitor alone prior to their surgery. A previous study showed that patients with triple-negative breast cancer treated with a PARP inhibitor alone as neoadjuvant therapy had good responses.^4,5

Here you are asking about a step beyond that. If you combine a PARP inhibitor with an immune drug, could you replace chemotherapy and surgery? This is an intriguing possibility whereby a non-chemotherapy-based therapy could potentially be used for patients with ovarian cancer upfront. However, it has to be carefully considered and developed. There have to be a series of studies with a high level of confidence that it is at least as good as the older chemotherapy options.

Question 4. It was determined in the phase 3 VELIA trial (ClinicalTrials.gov Identifier: NCT02470585) that homologous recombination deficiency (HRD) assay score did not predict outcomes in patients with newly diagnosed, advanced, high-grade serous ovarian carcinoma (HGSC).⁶ Do you think ultimately a benefit could be seen with PARP inhibitors in patients currently classified as homologous recombination-proficient (HRp)?

Answer
HRD cutoff has been set at a variety of levels. In this particular study it was revised from 42 to 33. It is likely that other levels may need to be considered rather than the current cutoff. We need to perhaps take a broader view and ask if HRD cutoffs are absolute with regard to predicting therapeutic benefit from a PARP inhibitor or if there are other values worth testing.

At a minimum, I do think there is value for using PARP inhibitors for patients who are HRD-positive. The next question would be, what is the best threshold for that? It is worth asking because there may be patients who could benefit from a PARP inhibitor that the current threshold would miss.

Question 5. In your view, which immunotherapy has (or combination of immunotherapies have) the most promise in ovarian cancer, and why? Could the use of neoantigen vaccines truly be feasible?

Answer
There may be subtypes of ovarian cancer, such as clear cell ovarian cancer, where even current PD-1/PD-L1 therapies may have good activity. There may also be a small percentage of patients, regardless of whether they have endometrioid or clear cell subtype, who have [microsatellite instability]-positive cancers and could benefit.

In high-grade serous ovarian cancer, these checkpoint inhibitors have not been all that active so far. The response rates have been modest. There could be several reasons for that. One reason could be that it is not the right checkpoint, and other checkpoints should be considered.

We know that the microenvironment of high-grade serous cancer is quite inflammatory. There are likely immune-suppressive pathways in these tumors that should also be targeted along with immune therapy. This is just one of the areas that needs to be addressed to improve effectiveness of immune therapy.

Neoantigen vaccines are an exciting avenue to consider. We just need to identify the best targets. This is a disease that does not have a huge mutation burden, but it does have a lot of copy number changes. The neoantigens that are being identified could be important for design of vaccines with robust activity.