Jennifer MacDonald, PharmD, BCOP: Let’s move on to our last section, which is a brief discussion of the future direction of PARP inhibitors. A lot is happening and a lot is coming for women with ovarian cancer. Dr. Monk, you’ve been in some of the combination trials with chemotherapy. The first one we tried was veliparib, but I don’t know the name of the trial.
Bradley J. Monk, MD, FACS, FACOG: Yes, the VELIA trial.
Jennifer MacDonald, PharmD, BCOP: Yes.
Bradley J. Monk, MD, FACS, FACOG: Here is the first thing. Rucaparib [Rubraca] is the only PARP inhibitor that does not have a first-line indication. They have a study similar to PRIMA but not identical. This study is called ATHENA, and it may report in January. That’s the first thing. The more options patients have, the better.
The second is that one can add PARP inhibitors to checkpoint inhibitors. We have another part of ATHENA, which is rucaparib/nivolumab [Opdivo], then we have another PARP inhibitor, niraparib [Zejula]/dostarlimab [Jemperli], then olaparib [Lynparza] with durvalumab [Imfinzi] or olaparib with pembrolizumab [Keytruda]. These are 4 studies that add PARP inhibitors to checkpoint inhibitors. Sometimes the checkpoint inhibitor is given with chemotherapy, and sometimes bevacizumab [Avastin] is required. ATHENA is in the maintenance phase. Suddenly we have 4 studies, some just in the maintenance phase, some with bevacizumab and some with a checkpoint inhibitor given with chemotherapy. All of these will likely report in 2022 or early 2023. That’s what’s short term.
As you know, Checkpoint Inhibitor was very disappointing. When we added avelumab [Bavencio] chemotherapy, it didn’t work. This is my study. When Katie Moore added it to bevacizumab on the front line, that didn’t work either. We have 2 negative first-line checkpoint inhibitor trials, but hopefully PARPs and checkpoint inhibitors will be the answer.
Jennifer MacDonald, PharmD, BCOP: Yes. And we can touch on that very briefly, but it doesn’t appear that ovarian cancer is very immunogenic, at least from what we’ve seen so far.
Bradley J. Monk, MD, FACS, FACOG: You think?
Jennifer MacDonald, PharmD, BCOP: From what we’ve seen, right?
Bradley J. Monk, MD, FACS, FACOG: Yes, from what we have seen.
Jennifer MacDonald, PharmD, BCOP: I can’t tell you how many times we get molecular profiles on patients – Sarah probably sees it all the time too – where PD-L1 [programmed death-ligand 1] is negative, TMB [tumor mutational burden] is low, MMR [mismatch repair]– competent and MSI [microsatellite instability] stable. We rarely see the patient who is PD-L1 positive. Or if so, it’s a CPS [combined positive score] of 1 and it’s not super exciting for us. There is definitely more to come with immunotherapy in ovarian cancer and some combinations with PARPs. It will be exciting to see all of this and the outcome to see if it makes a difference.
Bradley J. Monk, MD, FACS, FACOG: It will be. And that’s what I say. If it’s not bevacizumab or a PARP inhibitor, it doesn’t work in ovarian cancer. Hopefully we will get better.
Jennifer MacDonald, PharmD, BCOP: Yes definitely. I want to briefly touch on the mechanistic rationale for why bevacizumab with PARPs has been of particular interest to people. Sarah, maybe you can talk about it. Why did we go in this direction? Why did smart people go with this?
Sarah Hayward, PharmD, BCOP: I’ll defer to Dr. Monk. It would be better to answer him for a good solid answer.
Bradley J. Monk, MD, FACS, FACOG: I’ll defer to Jen because I don’t think there’s much justification other than that these are 2 effective treatments. If it’s not bevacizumab or a PARP inhibitor, it doesn’t work. And the addition seems to be more additive than synergistic. The resistance mechanisms do not overlap. Jen, if you have any comments on that, let me know.
Jennifer MacDonald, PharmD, BCOP: Yes. I have seen published data indicating that bevacizumab can possibly induce HRD [homologous recombination deficient] condition, which can make PARP inhibitors more active.
Bradley J. Monk, MD, FACS, FACOG: OKAY.
Jennifer MacDonald, PharmD, BCOP: Obviously, this stuff is preclinical. These are mouse models and things of that nature. But at least to some extent I understood that it came from some logic or line of thought that there might even be a role for this combination in the HRP [homologous recombination proficient] patient that you might possibly see. We haven’t seen that data or in patients because, as we said, PAOLA was part of the HRD patient population, so that’s yet to come. But one of the things that I’m hoping to come out of some of the data is that maybe it will come out and you’ll see an advantage for the combination in HRP, where I feel like we’re struggling in a to some extent to provide some options to patients that may help their long-term outcomes.
Bradley J. Monk, MD, FACS, FACOG: Yes. Very well said. Thank you.
Transcript edited for clarity