Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU medical oncologist and Associate Professor of Medicine at Northwestern University. I'm so excited to have here with me today, Dr. Arpit Rao, a friend, and colleague who is at the University of Minnesota, where he is an Assistant Professor of Medicine and a GU medical oncologist. Thank you so much for talking with me today, Dr. Rao.

Arpit Rao: Thank you, Dr. Morgans, for having me on and to UroToday as well. Thank you for the chance to talk about CASPAR.

Alicia Morgans: Always. Well, as you brought up, we would love to hear your thoughts on the Phase III clinical trial for patients with mCRPC, the CASPAR trial, that is actually launching as we speak, and really a brainchild of you and the team at the University of Minnesota to make a difference in combination therapies for men with mCRPC. Can you tell us a little bit about the study?

Arpit Rao: Yeah, so I'm really excited. This is almost the last three years of my life coming to fruition with the launch of CASPAR in the next few days. CASPAR is a randomized Phase III clinical trial of enzalutamide and rucaparib versus enzalutamide and placebo in first-line metastatic CRPC. We've been extremely fortunate to have the full endorsement and support of the Alliance as well as the NCI, and they are the sponsors of this trial and really excited to see it getting ready to launch nationwide in the next few days.

Alicia Morgans: Wonderful. Well, can you tell us a little bit about who these patients are, what they could have received previously in the metastatic hormone-sensitive setting, and confirm ... I think you said this is the first-line mCRPC setting, right?

Arpit Rao: Right. Alicia, as you know, now more and more of our treatments that used to be given for mCRPC are now going upstream and being used in hormone-sensitive disease or non-metastatic CRPC settings. For example, if you imagine a patient who received two-and-a-half years of abiraterone for hormone-sensitive disease, when that patient gets to mCRPC, is enzalutamide going to be enough? If the data from our sequencing efforts over the last decade in mCRPC, sequencing of abi after enza or enza after abi, if that data is any indication, then the answer is no. Enzalutamide alone or a single anti-androgen is not going to be enough in first-line mCRPC.

We really have to find ways to either bring newer treatment classes onboard for that line of disease or combine these based on strong biologic rationale. That's really the underpinning for CASPAR. For the last decade or so, it's been well-recognized in a growing body of preclinical data that when you take, even for prostate cancer cells that don't harbor any homologous recombination gene defect or DDR gene defect, if you expose these cancer cells to a combination of androgen deprivation and PARP inhibition, that it induces synthetic fatality, it induces synergistic cell death.

We've known about this phenomenon and in 2018, Dr. Clarke and his colleagues from the UK published and presented data on abiraterone and olaparib combination. It was a Phase II study, so limited by sample size and slightly different context, but it showed for the first time that in a clinical setting, all-comers, patients without any known DDR alteration, were benefiting from this combination as opposed to just abiraterone. That really was the big clinical push we needed to propose this ambitious Phase III study through the NCI and Alliance, and here we are.

Alicia Morgans: Wonderful. You're going to have how many men and they're all randomized, as you said to enzalutamide with or without rucaparib right?

Arpit Rao: Correct. So we'll take any patient who gets to mCRPC, doesn't need to have radiographically evaluable disease. They do need to have metastatic sites, but not through RECIST evaluable metastatic sites necessarily. The overall study has a PK sub-study, so the overall study is about 1,000 patients, and we'll split them into two groups of either one-to-one randomized to either rucaparib and enzalutamide or enzalutamide plus placebo.

Alicia Morgans: Fantastic. What are you looking for? Are you using progression outcome or survival outcome? What are you evaluating in this population?

Arpit Rao: We're looking at the co-primary endpoints, and there are a couple of other competing studies in this space. So as clinicians and clinical trialists around the country starting to think about which of these they want in their portfolio, I think it's important to recognize that CASPAR is really the only study that has overall survival as the co-primary endpoint. We're doing a hierarchical co-primary endpoint testing, where if we meet the PFS endpoint, then we have enough power, enough statistical power, to do overall survival analysis. That's going to be important, Alicia, as you know, because the question that's going to come up is, do we really need combination upfront? Or can we sequence them? That's a natural question that's going to come up. We've designed CASPAR to do answer that question directly head-on.

Alicia Morgans: Absolutely. You've also designed it to include men who don't have HR alterations, don't have these DNA repair defect mutations, and so they wouldn't be eligible to receive the sequence of rucaparib somewhere in their treatment algorithm unless they're on this trial. I think this will be really groundbreaking. I love that it is a definitive study, a Phase III that's going to help us answer this question, and then it has a survival endpoint as its final outcome. Because it's an NCI study run through the Alliance, but I'm sure that there is buy-in from the other cooperative groups in the system, this study is going to be open at potentially hundreds of centers across the United States, including some more community tech centers, some academic centers. As you said, it's launching as we speak. Can you give us a little sense of where some of these sites might be and how interested patients and their clinicians can get involved in this trial, first-line mCRPC again, if they are interested?

Arpit Rao: The other thing that may be very attractive ... So this would be open to large academic centers and community sites, and we've really kept that in mind at every step. So even the smallest of decisions about whether or not to get a new biopsy, whether or not to get a rebiopsy. We are using three genes. So BRCA1, BRCA2, and PALB2 status for stratification, for randomization. But we didn't want our clinician colleagues to struggle with biopsy and rebiopsy. We know how hard that is. So we've factored that in. So you just send in one set of archival tissue at the very beginning, and if we get an answer, we get an answer. Otherwise, we put those patients into an unknown category and randomize them still.

The other major attractive part is you don't have to worry like the majority of the studies, you now have to worry about whether they got abiraterone if there was a washout. As long as your patient did not get enzalutamide in a pre-mCRPC state, I think you're going to be good to go for CASPAR. That's really important. You could have treated them with abi, apalutamide, darolutamide, as long as you didn't give them enza or a PARP inhibitor, you're good to go. Then the on-treatment assessment is designed keeping our community colleagues' restrictions in mind. We're making it really easy for patients to be followed, for good quality data to be gathered from all kinds of sites. It's really designed for everybody.

Alicia Morgans: Wonderful. Well, we will post the link to the NCI clinicaltrials.gov site so that people can find you and find colleagues who might have the study open. Certainly, if there is interest, if you're a clinician at a particular site and you want to open it, there will be information for you to contact the sponsor, again, the Alliance Clinical Trials Organization to open the study if you are interested. I sincerely wish you and the team luck as you embark on this. It will be a few years before we have an answer, but every patient counts and the sooner we start, the sooner we'll know the answer. Do you have any closing thoughts or final messages to the viewers, patients, and clinicians who are interested in this trial?

Arpit Rao: I will say, I think there's a real urgency to finding the right treatment for this patient population, and we've designed a study with you all in mind. If you come on board, just strongly consider opening CASPAR at your institution and giving us feedback, reaching out to me personally at any time. It would be just fun to collaborate over the next few years.

¬ I will also say, Alicia, I couldn't have done this by myself by any stretch. There has been an extraordinary team of really experienced scientists, clinicians, everybody like Dr. Michael Morris, Dr. Chuck Ryan, Dr. Glenn Heller. There's a long list of extraordinary physicians and clinicians and others who've helped put together the study. I couldn't be more thankful for the support that we received from Alliance, Dr. Bertagnolli, and the NCI. So really appreciate everybody's help in this effort.

Alicia Morgans: Well, we'll need all the help we can get, 900 patients or 1,000. It's a lot of patients, but we as a prostate cancer community can get it done. Congratulations to you and all of your collaborators as you celebrate this initial success. I really look forward to talking to you along the way as we get preliminary and then final data to report to everyone. Congratulations on the launch of CASPAR, a Phase III trial for first-line CRPC for patients receiving enzalutamide with or without rucaparib with a survival endpoint. I think this is one that we're definitely going to have to be on the lookout for. Patients and clinicians, if you're interested, the clinicaltrials.gov website will be linked to this video. Thank you so much for your time, Dr. Rao.

Arpit Rao: Thank you, Dr. Morgans, and thanks for having me on UroToday. I appreciate it.