Novel Therapy for Relapsed/Refractory HR+ BC: IO Therapy and PARP Inhibition

Transcript:

Hope S. Rugo, MD, FASCO: We of course have other areas where we're going in terms of treatment for hormone receptor-positive metastatic disease after hormone therapy using immunotherapy; there's an ongoing trial, the KEYNOTE-B49 trial [NCT04895358], tell us just about that trial design, Komal?

Komal Jhaveri, MD, FACP: Yeah, in contrast to what we think about triple-negative breast cancer, we think about ER-positive tumors to be less immunogenic and perhaps a little colder, if you will, and not as hot as triple negative. Having said that, we've had attempts at looking at immunotherapy and its role in HR+ disease, and the very first data set was from the KEYNOTE-028 trial, where we did see overall response rates of about 12%. So, I think the KEYNOTE-B49 trial [NCT02054806] is trying to look at the role of immunotherapy in combination with chemotherapy, the way we do in triple-negative breast cancer, so when patients are doing first-line chemotherapy, this would be that patient population if they have PD-L1 positivity in this case, CPS [combined positive scores] of 1 or higher. These patients would then get randomized to receiving any one of the 3 chemotherapy drugs. It could be a taxane, both paclitaxine and now paclitaxel, it could be an anthracycline like liposomal doxorubicin, or capecitabine with or without pembrolizumab. And here, the 2 primary end points are progression-free survival, and also overall survival based on the PD-L1 statuses. It would be nice to look at whether we can establish it all for immunotherapy, even for our HR-positive disease. We did try and evaluate combinations of immunotherapy with CDK4/6 inhibitors based on pre-clinical data that suggested that there might be more a neoantigen so that we might be able to get that activity. We've tried to attempt that in multiple trials, tried to address that question but the risk-benefit ratio has not favored that combination in clinic. We'll see how this plays out for patients with HR-positive disease.

Hope S. Rugo, MD, FASCO: Yeah, I think it's an interesting question and certainly, we've identified some patients with HR+ disease that are more basal-like that benefit in the neoadjuvant setting in the I-SPY trial [NCT01042379] to immunotherapy. It'll be intriguing. We also, of course, have PARP inhibitors and combinations of PARP inhibitors—there's durvalumab, olaparib, and fulvestrant trial that's ongoing. How do you use PARP inhibitors in your practice and do you user PARP inhibitors for patients with somatic mutations? Where is this field going, Mark?

Mark Pegram, MD: It has also been another gamechanger the advent of PARP inhibition in metastatic breast cancer, and now in the adjuvant setting of course. It's been very impactful for patients with germline mutations; there are reports of responses, anecdotally, in patients with sporadic mutations in the BRCA genes as well. Moreover, there are other genes involved in homologous recombination DNA repair, like PALB2 that also seem to benefit from the class of PARP inhibitors generally. It's been very exciting. Regarding integrating PARP inhibition with immune checkpoint inhibition, as you rightly mentioned this trial of durvalumab, olaparib plus fulvestrant in patients with ER-positive metastatic disease is ongoing. It has a Simon 2-stage study design, following a safety run-in of 6 patients. There were no DLTs [dose limiting toxicity] in that safety run-in so the committee allowed them to move forward into the Simon 2-stage design, and now they've made it past the first step as well, which implies that there were indeed responders to get that far into a Simon 2-step trial. They've now treated about a 100-odd patients or so, and this was the first presentation of the study and the first interim analysis occurred in November 2021, based on the first 64 evaluable patients. It'll be exciting to see how this goes; it's phase 2 exploratory preliminary data. To be sure, we're not going to be doing this combination yet in clinical practice, but it's a very interesting next step and a logical path forward to try to integrate these with immune checkpoint inhibition in the ER-positive patient population.

Hope S. Rugo, MD, FASCO: I think it is really interesting and intriguing to me that they're not just looking at BRCA and PALB2 germline mutations, but also a whole host of somatic mutations, even ones that we thought maybe didn't work in our elaborate expanded trial that Nadine Tung [,MD, Beth Israel Deaconess Medical Center/Dana-Farber/Harvard Cancer Center] published from our consortium. It's going to be fascinating to see what that trial shows.

Mark Pegram, MD: Their eligibility was wide open with all those other genes, but in the latest amendment they focus back on the BRAC genes.

Hope S. Rugo, MD, FASCO: Probably because they didn't see the good mutation responses. I don't know how you do it in a single-arm trial, but it's going to be interesting.

Transcript edited for clarity.