Emerging Treatments in Ovarian Cancer
Stephanie V. Blank, MD
New York, NY
Gynecologic Oncology (Ovarian, Uterine, and Cervical Cancers)
Hospital and Institutional Affiliations
Mount Sinai Health System
Question 1. What is your view on the addition of bevacizumab to maintenance regimens for BRCA-associated ovarian cancers?
PAOLA-1 (ClinicalTrials.gov Identifier: NCT02477644
) looked at frontline maintenance bevacizumab plus olaparib vs bevacizumab plus placebo, and found bevacizumab plus olaparib to provide a [progression-free survival] benefit, but there was no olaparib-alone arm, so based on this trial, I could not comment on whether adding bevacizumab to olaparib offered an advantage over olaparib alone for BRCA-associated ovarian cancers.
Some post-hoc analyses were presented at the [the American Society of Clinical Oncology 2020 (ASCO20) Virtual Scientific Program] — one looking only at the BRCA-associated ovarian cancers in PAOLA — but again, no olaparib-only arm makes it not possible to determine the effect of adding bevacizumab to olaparib in these patients.
Another modeling study looked at the patients [with BRCA
-mutated disease] from PAOLA and compared them to SOLO-1 (ClinicalTrials.gov Identifier: NCT01844986
) patients and determined that the dual therapy was better, but to me, this is still cross-trial comparison, even if you call it modeling or indirect comparison, so I do not think you can say anything definitively. The SOLO-1 data on olaparib alone for maintenance in patients [with BRCA
-mutated disease] were quite remarkable.1
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 poly(ADP)-ribose polymerase (PARP) inhibitors (PARPis), if any?
There have been a few frontline trials presented in the last several months raising the question of which patients are suitable for frontline PARP inhibitor maintenance. This widens the group of people for whom frontline PARP maintenance may be helpful. We are still working out the best biomarkers to use to determine candidates for maintenance. Of course the PRIMA trial (ClinicalTrials.gov Identifier: NCT02655016
) showed that biomarkers did not determine whether a patient would benefit from PARP maintenance, but biomarkers do help determine the magnitude of the benefit and can help in decision making about the risk vs benefit of PARP maintenance.2
In terms of using PARP inhibitors as treatment, at [the ASCO20 Virtual Scientific Program], there was 1 trial looking at cediranib and olaparib (as opposed to platinum-based chemotherapy) for people with platinum-sensitive cancer. The PARP regimen wasn’t superior, but it did have activity similar to chemotherapy and may, therefore, be considered another alternative to chemotherapy. That is a bit of a change. Before, we would use olaparib only for treatment of people with BRCA
mutations and maintenance PARP in other patients.
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?
At this point in time, it is too early to say that. I do not believe that these agents have been studied in the front line independent of chemotherapy. They are generally added to chemotherapy, and trials looking at these combinations are ongoing. I don’t think that a trial with a nonchemotherapy arm for frontline ovarian cancer would be feasible, and this would be necessary to forgo frontline chemotherapy as [the] standard of care.
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).3
Do you think ultimately a benefit could be seen with PARP inhibitors in patients currently classified as homologous recombination-proficient (HRp)?
The answer is, yes, potentially. HRD is a decent biomarker but not a perfect biomarker. We are always looking for more biomarkers to figure out who will respond to PARP inhibitors.
The PRIMA trial showed activity in patients who were homologous recombination-proficient. What degree of activity is needed? Nothing is definitive at this point. It is provocative to think that HRD is not going to be the only biomarker because it makes so much sense in terms of the mechanism of the drug.
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?
At this point in time, I haven’t seen a single-agent immunotherapy as being a massive success in ovarian cancer — ovarian cancer has not enjoyed the same success with checkpoint inhibitors that some other cancers have seen, possibly because it has a lower mutational burden. We are probably going to end up combining some form of immunotherapy with another agent, or looking at different forms of immunotherapy — perhaps something adaptive, for example, [or] vaccines post chemotherapy. Again, there are trials ongoing and we will know a lot more when we see those results.
- Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505.
- González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402.
- Swisher EM, Kaufmann SH, Birrer MJ, et al. Exploring the relationship between homologous recombination score and progression-free survival in BRCA wildtype ovarian carcinoma: Analysis of veliparib plus carboplatin/paclitaxel in the velia study. Submitted to: Society of Gynecologic Oncology (SGO) 2020 Annual Meeting on Women’s Cancer. Abstract LBA 6.