TIAN ZHANG:

Welcome to VJ Sessions, Session on GU ASCO updates. I’m Tian Zhang, Associate Professor at UT Southwestern in Dallas, and I’m here with my good friend Dr. Tagawa.

SCOTT TAGAWA:
Hi, I’m Scott Tagawa, a medical oncologist at Weill Cornell in New York.

TIAN ZHANG:
And we wanted to highlight some of the abstracts and key trials that have been presented at GU ASCO this weekend. So first, I thought it was a great prostate day on Thursday. And can you share with us some of your thoughts about some of the key PARP inhibitor trials, the two that were presented: PROpel and MAGNITUDE?

SCOTT TAGAWA:
Sure. It’s been an exciting meeting for prostate cancer in general. A lot of randomized Phase III data across the board. We know that there’s a benefit to PARP inhibitors, particularly in pretreated patient populations that are molecularly selected. There were two Phase III studies presented at this meeting with ongoing additional randomized trials that looked at both molecularly selected, as well as molecularly unselected patients, in combination with AR pathway targeting, these two trials happened to be with abiraterone.

Very briefly, the PROpel study was an all-comer viewpoints not exposed as general to AR pathway inhibitors, potent AR pathway inhibitors, and was positive in all-comers. It looked to be a little bit more of a benefit, not surprisingly, in those with HRD. But in all comers, there was an improvement in progression-free survival. On the other hand, the MAGNITUDE trial using niraparib enrolled a patient population that looked to be sicker. So we can’t really compare across clinical trials, but looked to be sicker. It had two separate parallel trials. One of which was an HRD-negative patient population that used a futility analysis that was mostly driven by PSA, even though the primary endpoint was rPFS. In a case that arm was decided to be futile, the arm with HRD did move forward and was positive for rPFS in combination with abiraterone, about a quarter of whom had already been exposed to abiraterone and/or another AR pathway inhibitor prior to enrollment.

TIAN ZHANG:
What a great summary. And what do you think are some of the key takeaways? Should we be combining our PARP inhibitors with abiraterone for frontline castration-resistant prostate cancer at this point?

SCOTT TAGAWA:
So I think it’s an option. So there’s some scientific rationale of the interaction between PARP and AR. The PROpel trial came on the heels of a positive randomized Phase II, with those results more or less replicated in the Phase III trial. The hazard ratio was very similar. So as a clinical trialist, I like to believe that. And there was a trend for an overall survival benefit. You know, I don’t necessarily want to say that MAGNITUDE was negative, but brought up some questions. So you know, as someone that will have a patient sitting in front of me, I hope to have that as an option. I’m not sure at this point if I’m ready to give that combination to all comers. The good thing is that we have additional trials with AR pathway inhibitors and darolutamides with or without both in a talazoparib setting in a pharma trial and an NCI-cooperative group trial called CASPAR and darolutamides with rucaparib or placebo that hopefully will shed additional light.

TIAN ZHANG:
Yeah, those are great insights. And I think, you know maybe for a biomarker-selected population, where we’ll be thinking more about this combination. Wonderful. What other Phase III study? We also saw the results of ARASENS and long anticipated results of darolutamide ADT and docetaxel. Can you talk a little bit about that?

SCOTT TAGAWA:
Yeah, so first of all what is completely non-controversial is that someone walking in the door with metastatic prostate cancer untreated call it non-castrate hormone-sensitive, castration-sensitive, all different terminologies, for now called synonyms, it’s very clear that intensified therapy is superior. So very few patients, maybe if they’re older and sicker, but very few patients should be getting monotherapy or ADT with an old fashioned non-steroidal anti-androgen. That’s for sure. Now we have two trials looking at a triplet. So with the backbone coming off of the initial part of STAMPEDE, plus the the CHAARTED studies of ADT docetaxel as a backbone, adding an opponent AR pathway inhibitor either initially in PEACE1 with abiraterone, or now darolutamide with ARASENS, that that triplet is superior in terms of survival to the doublet, if the doublet is ADT docetaxel.

So I put these trials together and would say that a standard of care for a population, probably especially with high volume disease, we haven’t seen those subsets. I honestly haven’t fully delved into the New England Journal paper yet, just saw the presentation, but my sense is those that are high-risk might have that benefit. What we don’t have is, is that significantly better than the ADT plus potent AR pathway inhibitor? So what’s the contribution of docetaxel? I think it is like a meaningful contribution in the subset. I’m just not exactly clear who that is right now.

TIAN ZHANG:
Maybe for the patients that we may add docetaxel to, because the control cohort for ARASENS, right, was ADT with docetaxel. So everyone received chemotherapy and so maybe the patients that we’re currently thinking might be candidates for docetaxel up front may also benefit from continued AR suppression and AR antagonism after their chemotherapy. That’s my takeaway from ARASENS. Good. Awesome. Do we wanna switch to kidney cancer trials?

SCOTT TAGAWA:
Sure. So we’re during the middle of the kidney cancer… early, actually, on the kidney cancer day. The landscape of management of advanced kidney cancer has changed multiple times. Most recently with a number of different combinations. So what are you looking forward to in terms of updates for advanced kidney cancer?

TIAN ZHANG:
Sure. So in advanced kidney cancer, we actually saw the results from an investigator-led trial from Matt Zibelman and the team at Fox Chase this morning, where they looked at kidney cancers treated with axitinib with nivolumab. And in this patient population, there was actually a very high, 60% almost, objective response rate. And so, we’re really thinking about how do we use our combinations effectively in this upfront setting, right? So there’s multiple VEGF IO combinations now approved and thinking about these different combinations, they made a great point, I think, of saying, you know, we have multiple agents and VEGF inhibitors and so if we can use our axitinib early on, we can save some of the mechanisms for with cabozantinib or lenvatinib for later lines of therapy. Of note, in their trial, they had a large proportion of favorable risk population of patients. And so in that risk population we’re thinking they’re more antigenically driven, less inflamed and therefore, perhaps set up more for responses to VEGF IO combination therapies. And so, certainly adds more data for how we think about VEGF IO combinations in the frontline.

SCOTT TAGAWA:
So just a little bit of background, and a plug that I’ll shift over to you. So I happen to know the institutions that were enrolling, that a lot were giving double IO Ipi/Nivo for the intermediate and high risk. How might we improve that in the future?

TIAN ZHANG:
Oh, sure. So, you know, we are, all of us, giving a lot of dual checkpoint inhibition for intermediate and poor risk disease, and a lot of our trials now are built on ipilimumab and nivolumab. I am somewhat biased. I have one of the Phase III trials that we’re running through the Alliance Cooperative Group called PEDIGREE. That’s hedged on induction of Ipi/Nivo followed by nivolumab, or nivolumab with cabozantinib, sort of in a sequencing approach. But we’ve seen a series now, of triplet trials in the frontline setting as well, COSMIC-313 just closed to accrual last year. And so this was ipilimumab, nivolumab, with cabozantinib in the frontline setting, all three. And so can we get a little bit earlier response rates in the earlier setting with the duration of responses of our dual checkpoint inhibitors. And so, that’s a study that I’m looking forward to the results of. There is an ongoing study now with triplet therapy, belzutifan, lenvatinib, and pembrolizumab, or the triplet of lenvatinib, pembrolizumab and quavonlimab, which is the other CTLA-four inhibitor and seeing if we can build on what we’ve learned from lenvatinib pembrolizumab combination. So all of these trials really are trying to intensify therapy. I think we’re all learning from each other in different disease states to try to add to our therapies in the frontline, to get to as good a response as possible from the early setting. And then we also have a really great trial in the cooperative groups, looking specifically at the question of consolidative surgery of nephrectomy. And so if we can get good responses and with immunotherapy combinations, when can we operate on these patients and do the consolidative nephrectomy to the primary tumor. So I think that’s also a very important question and one that Dr. Vaishampayan is leading called the PROBE Trial. So we’re very excited to enroll to that, too.

SCOTT TAGAWA:
Speaking of surgery, if we’re thinking about earlier stage disease, we now have some positive data. What are some updates in early stage disease?

TIAN ZHANG:
Sure. So one, we are anticipating the results of a trial called NEOAVAX later this afternoon of neoadjuvant treatment with avelumab and axitinib, one that Axel Bex is presenting to us from the United Kingdom. I think this trial is going to be important in terms of thinking about locally advanced or local disease that needs a little surgical debulking, or systemic debulking if you will, to get to a better surgery. And well, there’s about five neoadjuvant trials currently in the landscape. They’re all Phase II, relatively small, different combinations, but should really add to our understanding of how can we shrink tumors before they go to surgical resection. And hopefully, some of our very active therapies can actually do a better job of shrinking tumors and make it an easier surgery for our surgeons.

Now in the postoperative setting, we also saw the results of KEYNOTE-564, adjuvant pembrolizumab versus placebo last year and we’re going to see the added results, the 30 month follow up, at this afternoon’s session as well. Where we think we’re going to see that the 30 month follow up continued to have ongoing disease-free survival benefit in patients who are treated with pembrolizumab versus placebo. And so my understanding is that we’re still looking at delay until disease recurrence and not necessarily enough events on the overall survival curves, but I’m really looking forward to the data.

SCOTT TAGAWA:
So in summary, ASCO GU 2022 has been exciting. One of the most exciting features is the ability to see each other in person, but as in the context of scientific advances that are translating to advantages for our patients.

TIAN ZHANG:
Thank you so much and we appreciate you and everyone joining us today.

[END]

Recording date: 19-Feb-2022; Feature publication date: 11-Mar-2022.

Tian Zhang

Research funding: Acerta, Novartis, Merrimack, Abbvie/StemCentrx, Merck, Regeneron, MiratiTherapeutics, Janssen, Astra Zeneca, Pfizer, OmniSeq, Personal Genome Diagnostics, Astellas

Advisory Board: Merck, Exelixis, Sanofi-Aventis, Janssen, Astra Zeneca, Pfizer, Amgen, BMS, Pharmacyclics, SeaGen, Calithera, QED Therapeutics, Eisai, Aveo

Consultant: Pfizer, MJH Associates, Vaniam, Aptitude Health

Scott Tagawa (N.b. Disclosures below were provided in 2021)

Research support (to Weill Cornell since 2007): Sanofi, Medivation, Astellas, Janssen, Amgen, Progenics, Dendreon, Lilly, Genentech, Newlink, BMS, Inovio, AstraZeneca, Immunomedics, Aveo, Rexahn, Atlab, Boehringer Ingelheim, Millennium, Bayer, Merck, Abbvie, Karyopharm, Endocyte, Clovis, Seattle Genetics, Novartis, Gilead, POINT Biopharma.

Consultancy (since 2007): Sanofi, Medivation/Astellas, Dendreon, Janssen, Genentech, Bayer, Endocyte, Eisai, Immunomedics, Karyopharm, Abbvie, Tolmar, Seattle Genetics, Amgen, Clovis, QED, Pfizer, AAA/Novartis, Clarity, Genomic Health, POINT Biopharma, Blue Earth Diagnostics, AIkido Pharma, Telix Pharma, Convergent Therapeutics.

Unpaid consultancy: Atlab Pharma, Phosplatin Therapeutics, Amgen, Ambrx