Alicia Morgans: Hi. I am delighted to have here with me today Dr. Arpit Rao, who is an Assistant Professor of Medicine at the University of Minnesota. Thanks so much for talking today.

Arpit Rao: Happy to be here, Alicia.

Alicia Morgans: Of course. I'm going to talk to you about some of the new personalization that's been happening in prostate cancer. We've had data trickling in over years for things like PARP inhibitors. I'd love to hear your thoughts because we've got some big data that's coming out around PARP inhibitors very shortly, and then we can talk a little bit more about where things are going in the future and how we're continuing to use that data to help people. Tell me where do things stand with PARP and what are you thinking about in terms of personalizing medicine for this population?

Arpit Rao: Yeah. PARP inhibitor, just for the people who don't know much about them, they are this class of drugs that are really important in DNA repair. If cancer cells have an inherent defect in repairing their DNA, when you add PARP to the equation, it creates what's called a synthetic lethality, which means the cancer cells are more sensitive and then they die because of PARP inhibition exposure. There've been a number of trials. Over the last five years, we've figured out that, as you know, about 15%, as much as 15%, of metastatic castration in prostate cancer has some kind of HRR defect, so homologous recombination or DNA damage response defect, and these are excellent candidates for PARP therapy.

There've been a number of trials that have been ongoing. For example, one of these trials is what's called a PROfound study. We recently saw a press release from the manufacturer. This is a randomized Phase III trial of men with metastatic CRPC who've had at least one line of novel antiandrogen, so abiraterone or enzalutamide, and then they get randomized to either Olaparib, which is a PARP inhibitor, or the second-line standard of care treatment, which is typically abiraterone or enzalutamide. The top line results, and again, this data is embargoed for the next couple of weeks, but the top line results, there is benefit in Olaparib in the setting.

Olaparib performed better in the primary endpoint, which is radiographic progression-free survival, compared with the standard of care. That's really exciting. Also goes back to the results we saw with TRITON2, Wassim Abida, that data that was shared a few months ago, and then last year with TOPARP-B, the results that came out, and those were consistent. There is benefit. There is improved responses in HR and mutant patients. In TOPARP-B for example, there's 54% radiographic response rate. That's really impressive. It's only in patients with one of 15 of the HR gene mutations, predominantly BRCA1, BRCA2, PALB2, some ATM, so the usual suspects so to speak, but that's where the story with monotherapy is evolving.

Alicia Morgans: Absolutely. I think it's important for us to know that there are these specific DNA repaired defect mutations that we should be thinking about and that's why genomic testing is so important for men with prostate cancer. These mutations can happen in the germline, so the things that people pass down from parent to child, and also in the tumor itself. You don't need to have two hits for these mutations or for these medications to work. You can have one or the other. We do think if you have both actually, you may be even more sensitive, but it's not required. The most common, and actually the most sensitive, seems to be BRCA2, which is really encouraging.

But what about patients who don't have these alterations because I think we've seen a study where there may be a signal in patients who don't have these alterations?

Arpit Rao: Right. All of those are great points. We don't look at our tens and hundreds of thousands of patients and say, "We'll only help 15% of you guys." There's this really interesting phenomenon as it pertains to BRCA2. Even going back several years or several decades, we've known that androgen receptor signaling is really important in DNA damage response. Having normal levels or adequate levels of testosterone in a normal cell or cancer cell helps it repair DNA. When you interrupt that, when you deplete that testosterone level, there is increase in DNA breaks, typically double-stranded DNA breaks. That's similar to BRCA, that's similar to when BRCA is lost. We've known that by depleting the cancer cells with androgen and combining PARP inhibition, there's something to it.

That had been around for the last several years in preclinical models. There's synthetic lethality in that setting. For the first time, our colleague Dr. Noel Clarke in the UK, he designed this randomized Phase II trial looking at... Which is a double-blinded trial of abiraterone plus Olaparib or abiraterone and plus placebo. This was more than 150 odd patients, second-line or third-line, so most patients should have received at least one novel antiandrogen and at least from one chemotherapy. 99% of patients did get chemotherapy in that trial and so on. But for the first time in unselected patients, meaning all comers, there was a trend towards improvement in radiographic progression-free survival in the combination arm. It was 13.8 months versus 5.8 months or something like that in the overall population.

Alicia Morgans: It was so interesting too that that difference and radiographic progression-free survival held for those patients who had verified DNA repair defect alterations. They did a subgroup analysis. They also showed similar radiographic progression survival curves for patients who were wild type, and they both had the separation of curves with the combination of abi and Olaparib doing better than abi alone, which I thought was really interesting.

Arpit Rao: Correct. I remember sitting in ASCO 2018 where this data was shared and there was excitement when we looked at it because we thought maybe it's all driven by the HR mutant population. But in reality, and these were not post hoc analysis. These were built in. These were powered for detecting that difference in the HR wild type population. When we saw that trend towards benefit, we immediately jumped up and said, "Hey, we got to do something about this."

Alicia Morgans: Absolutely. Now, I do remember seeing the survival curve, the overall survival curve. There was actually not a difference. Those curves came back together. No benefit necessarily for the combination. However, you could have any number of different treatments. When we're looking at survival, there are other things intervening. At least, at the very least, hypothesis-generating and something that I am certainly eager to see taken forward. I think you are taking it forward, right?

Arpit Rao: Yeah. Yeah. There's been lots of interest in this space over the last year. I'll talk about that important question that you posed about survival. Survival in these kinds of studies obviously is diluted by a number of factors. The question that comes to my mind is should we do combination upfront or should we sequence them? Maybe even give PARP inhibitor upfront and then do the AR antagonist in sequence. We don't know what the answer is. We definitely need randomized Phase III clinical trials that are powered for overall survival to be able to answer this question. In that sense, we are working with the NCI and through Alliance. We're fortunate enough to have the support of Alliance to develop a randomized Phase II-III trial of enzalutamide and rucaparib in the setting in frontline metastatic CRPC. We're hoping we've gotten to a point where we're hoping to launch this trial early next year.

Alicia Morgans: Absolutely. It's been approved by the steering committee.

Arpit Rao: Correct.

Alicia Morgans: It's in protocol development.

Arpit Rao: Correct.

Alicia Morgans: We as a community can start looking for it probably summertime next year. Let's hope. Fingers crossed.

Arpit Rao: Correct. Yeah.

Alicia Morgans: The good thing about cooperative group trials is that they are open at many centers across the country. You can find information about this trial on clinicaltrials.gov in maybe six to eight months. Anyone who's can go look for that for metastatic castration-resistant population. What is the name of this trial? I know you're always good with names.

Arpit Rao: We decided to call this the CASPER trial.

Alicia Morgans: Great.

Arpit Rao: That's because co-inhibition of androgen receptor and PARP.

Alicia Morgans: Wonderful.

Arpit Rao: So, CASPER.

Alicia Morgans: Wonderful. Easy to remember CASPER. Everyone should be looking out for it. Any closing thoughts or new directions, CDK12, or other things that you want us to keep our minds on as we look to the horizon?

Arpit Rao: Yeah. The CDK12 story is very fascinating because that's another population that are [inaudible 00:09:33] A few years ago, we identified this as kind of a more immunogenic subtype of metastatic prostate cancer. We have a trial through the industry that's looking at CDK12 mutant biallelic loss cohort and giving those patients CDK4/6 inhibitor in combination with a PD-L1 inhibitor. That would be a trial that's on the horizon. Very excited about it because that's another group to target really well.

Alicia Morgans: Absolutely. Well, thank you so much for sharing your thoughts. I am eager to see where all of these things go, and we'll continue these conversations over time, but thank you. Thank you again.

Arpit Rao: Thank you for giving me the opportunity, Alicia. This is great. Thank you so much.