Zachary Klaassen: Hi, my name is Zach Klaassen. I'm a Urologic Oncologist at the Georgia Cancer Center in Augusta, Georgia. We are live at ASCO 2024 in Chicago. I'm delighted to be joined by Dr. Deepak Kilari, Medical Oncologist at Medical College of Wisconsin. Deepak, thanks so much for joining us today.

Deepak Kilari: Zach, thank you so much for having us.

Zachary Klaassen: I'm excited to talk to you about your trial you presented at ASCO, and this is basically a phase two looking at enzalutamide plus five ARIs for castrate sensitive prostate cancer. So just by way of background, how did this trial come to be fruition?

Deepak Kilari: Thanks, Zach for that question. So I've had the pleasure of training with a geriatric oncologist. Her name is Supriya Mohile, and when I was training with her, her specialty was both GU as well as Geriatric Oncology. And she was seeing men who were in their 80s and 90s. And these men either had high-risk biochemical relapse, or metastatic castrate sensitive prostate cancer. And all of them are castrate sensitive. And what I was surprised to see was that she was not putting them on hormonal therapy, she was putting them on bicalutamide and finasteride. So that was my first exposure to bicalutamide and Finasteride. And I had asked her, why are you doing this?

Zachary Klaassen: Yeah.

Deepak Kilari: And that's when she sort of said that, "Well, these guys are really frail. If I put them on hormonal therapy, there's a very high probability that these guys who are staying at home by themselves will end up in a nursing home."

Zachary Klaassen: Sure.

Deepak Kilari: I mean, they're taking care of their spouses, they're taking care of their houses. So it's very difficult for them to tolerate ADT at this age when they're already frail. So that sort of piqued my interest. So what I did was when I was a fellow, I actually looked up our own institutional site. I trained at University of Rochester, and we looked at the institutional database and we found over 40 patients that had gotten bicalutamide and Finasteride instead of ADT for hormone-sensitive prostate cancer.

Zachary Klaassen: Okay.

Deepak Kilari: And the median time to progression was around 10 to 14 months, or I would say around 14 months. But all of them did progress and they didn't really have great options. So then I looked back at the data and asked myself, did anybody else do bicalutamide and Finasteride? And I was surprised that there was a lot of studies that were done with bicalutamide monotherapy in the 1990s. So what they found at that point was that bicalutamide monotherapy was better tolerated. However, when they did a meta-analysis looking at bicalutamide versus ADT, bicalutamide monotherapy was inferior in terms of survival. So based on that, the NCCN guidelines back then did not recommend bicalutamide monotherapy for castrate sensitive prostate cancer. So then I asked myself, why was she adding Finasteride?

Zachary Klaassen: Right.

Deepak Kilari: Or why dutasteride? So there were studies that looked at peripheral antigen blockade. So we all know complete antigen blockade is ADT plus ARSI, like apalutamide and solutamide or even bicalutamide.

But the goal of these studies was to sort of see if we can not deplete testosterone in men who are older and frail. There were several studies actually that were done that looked at bicalutamide and Finasteride, Flutamide and Finasteride, and in all of these studies, what they found was that there were studies where they were given upfront Finasteride. So it wasn't at progression.

Zachary Klaassen: Right.

Deepak Kilari: But there was a benefit. Or if you look at historical data, the other time to progression was longer with bicalutamide and Finasteride, but there was one very elegant study that looked at adding Finasteride at a subsequent time point, and there was a further decline in PSA with additional of finasteride. So the hypothesis was that these ARSIs actually brought testosterone from getting into the cancer cell. But then we have Finasteride, which is basically an ARA that prevents the conversion of testosterone to dihydrotestosterone. We all know that dihydrotestosterone is the more potent form of testosterone that causes self-proliferation. When I was in a fellowship, I sort of said, "This data looks great."

Zachary Klaassen: Yeah.

Deepak Kilari: But if patients progress in 10 to 14 months what are we going to do? Are we going to put these guys on hormonal therapy?

Zachary Klaassen: Right.

Deepak Kilari: So then we stepped back and right around that time, enzalutamide was approved. So we sort of said, "Why can't we do a study for enzalutamide and Finasteride?" And right around the time that we were proposing the study, Dr. Tombal had done a study with enzalutamide monotherapy by itself. It seemed very promising, but at the same time, we just didn't have long-term follow up data.

Zachary Klaassen: Right.

Deepak Kilari: So when we proposed our study, we sort of wanted to look at enzalutamide in combination with dutasteride. So not just Finasteride, but dutasteride. And the rationale for dutasteride was it blocks both Alpha-1 and Alpha-2, and it's supposed to be more potent. But through the conduct of the trial, we realized that dutasteride was not covered by insurance companies because it's not approved for prostate cancer.

Zachary Klaassen: Right.

Deepak Kilari: So we allowed for substitution with Finasteride. And basically the goal of the trial was, can we prevent patients going on ADT by giving enzalutamide and Finasteride or dutasteride. Dutasteride preferential.

Zachary Klaassen: So we all have these patients rolling around the, you're worried about starting anything on them. So I think it's important for our listeners to understand what was the inclusion criteria the patients you were really looking for for this trial?

Deepak Kilari: Thanks, Zach for that. So we took men who were castration-sensitive, so all men have to have a testosterone of more than 50. And what was different between other trials and our trial, and I think I really want to highlight this, is that all patients had to have a baseline comprehensive geriatric assessment.

Zachary Klaassen: Yeah, good point.

Deepak Kilari: And they had to have that. And either the geriatric oncologists had to say they are frail and or the provider actually has to say that they're at a very high risk of side effects from ADT.

Zachary Klaassen: Right.

Deepak Kilari: So a patient can't just say, I don't want to get ADT. I can go on this trial. So we basically had mandated that either CGA or a provider felt that the patient was not a right candidate for ADT.

Zachary Klaassen: I see.

Deepak Kilari: So we included two courts of men. We included men that had high risk biochemical relapse, that's men that had PSA, that was increasing on three separate occasions, a PSA of more than two, and a doubling time of less than nine months. Or we took men that had metastatic prostate cancer. It could have been recurrent prostate cancer or it could have been de novo prostate cancer. And as you know, ADT was a standard of care for all of these men-

Zachary Klaassen: Right.

Deepak Kilari: ... until more recently.

Zachary Klaassen: How about outcomes? I know you talked about looking at preventing men from going on ADT. Was that your primary outcome? And maybe highlight some of the second draft as well.

Deepak Kilari: Yeah. So the primary outcome at the time we designed the trial, that was our intent. How long can people stay off of ADT? So our primary outcome was time to PSA progression or PSA progression survival. And we had secondary endpoints like time to PSA nadir, absolute PSA nadir, and then absolute change in PSA. But we also had some very interesting exploratory endpoints like change in comprehensive geriatric assessment domains.

Zachary Klaassen: Right. Yeah.

Deepak Kilari: So we just didn't look at geriatric assessment baseline and say, "These guys are fit, frail, or vulnerable." But we sort of did geriatric assessments at multiple time points at week zero, week 13, week 27, week 61.

Zachary Klaassen: Yeah.

Deepak Kilari: So to assess not just what the patients tell us in terms of the side effects, but are they deteriorating physically as well? And we also looked at their bone health over time.

Zachary Klaassen: Great. Take us through some of the highlights of the results.

Deepak Kilari: Our hypothesis was that patients wouldn't stay on this treatment for more than two years because typically metastatic prostate cancer, you know that ADT works only for two years.

Zachary Klaassen: Right.

Deepak Kilari: So we are pleased to say that the median PSA progression-free survival was not reached.

Zachary Klaassen: Wow.

Deepak Kilari: So the study started off, I designed the study when I was a fellow, and then the study started off in 2014, and the data cutoff is as of December 2022.  And so we have a good six to seven year follow-up period. And of the 43 patients on trial, almost more than half of them are still on trial.

Zachary Klaassen: Wow.

Deepak Kilari: Suggesting that, I mean, clearly the median PSA progression-free survival is not reached. And that was very encouraging for us because we didn't expect enzalutamide and ARI to work that long.

Zachary Klaassen: Yeah, absolutely.

Deepak Kilari: And then we also looked at absolute PSA nadir, it was 0.02 or less most of them had undetectable PSAs. We also looked at a percentage change in PSA. And what we found was that most of them had, I would say all of them almost had a 98% decline in their PSA. But what we also looked at is we looked at change in testosterone. These are castration naive men. So when we gave them enzalutamide and ARIs, their testosterone levels actually increased.

Zachary Klaassen: Right.

Deepak Kilari: So there were men that had testosterone in their 800 and 900, and men were really appreciative that they were able to do stuff. I mean, not feel tired all the time not have sexual issues and everything else. And we also looked at change in dihydrotestosterone because the role of these five alpha-reductase inhibitors is to decrease the dihydrotestosterone. And we did find that there was a significant decline in dihydrotestosterone for these patients. What was really more interesting is, so those are the main results, and we can talk about the adverse events and everything else down the lines.

Zachary Klaassen: Yeah, I think that just from a high level, what was your interpretation of the tolerability? These are frail men by definition, but staying on treatment for upwards of six to eight to almost 10 years now. Right?

Deepak Kilari: Yep.

Zachary Klaassen: What's your impression at a high level of the tolerability of the combination?

Deepak Kilari: I would say the treatment was well tolerated. There were side effects.

Zachary Klaassen: Sure.

Deepak Kilari: But the side effects were manageable. So the most common side effect that we did see was fatigue. Then we also saw gynecomastia, and we've seen the same with EMBARK.

Zachary Klaassen: Sure.

Deepak Kilari: We've seen the same with Dr. Tombal's study. When you give ARSI's in a monotherapy fashion, we do see gynecomastia. So we did see gynecomastia.

Zachary Klaassen: Yeah. And even the five ARIs can cause some of that too.

Deepak Kilari: Yep. So both of them obviously cost the gynecomastia. We were offering patients prophylactic breast radiation. Patients didn't want it. We were offering them radiation through the treatment course.

Zachary Klaassen: Right.

Deepak Kilari: So it was mostly tolerable gynecomastia that patients didn't want to change anything.

Zachary Klaassen: Yeah.

Deepak Kilari: So besides fatigue, gynecomastia, we saw hot flashes as the main side effect as well.

Zachary Klaassen: Sure.

Deepak Kilari: People often ask me, "Well, these are frail patients." I mean, all of these are frail patients. Did we see a lot of dose reductions, dose interruptions? So we did see dose reductions and interruptions, but I would say that dose reductions are probably seen in around 20% of patients. And those interruptions were seen in 30% of patients. And 10% of patients had to stop treatment due to adverse events.

Zachary Klaassen: I see.

Deepak Kilari: But again, you have taken into account that these are very frail men.

Zachary Klaassen: Yes.

Deepak Kilari: And what I want to highlight more is what we did on the geriatric assessment.

Zachary Klaassen: Absolutely.

Deepak Kilari: Because people often say, "Well, the doctor said you're frail. Does that really mean you're frail?" So we did a geriatric assessment and we found that 70% of patients had two or more impairments in their baseline CGA domains. 20% had IADL impairments. So basically they could not perform their instrumental activity of daily living. And these are the patients that we put on trial.

Zachary Klaassen: Yeah.

Deepak Kilari: 56% of them had cognitive impairment.

Zachary Klaassen: Wow.

Deepak Kilari: At baseline. I mean, these are patients that actually have cognitive impairment that are picked up by Blessed and Mocha, which are validated geriatric tools.

Zachary Klaassen: Right.

Deepak Kilari: 10% of patients actually had falls at baseline. Right, I mean, these are guys who are already falling down. Recording falls. 98% of these men had more than five medications at baseline, so they were polypharmacy users.

Zachary Klaassen: Right.

Deepak Kilari: So again, all highlighting the fact that this is a very frail population to begin with.

Zachary Klaassen: Yeah. No, that's great. I think Phase-2, 43 patients, great data, great hypothesis generating. What's the next steps for this combination?

Deepak Kilari: So I think the study should be expanded to a bigger study because we all, as you pointed out, we all have men who are not great candidates for ADT. And all these trials nowadays are just focusing on doublets and triplets and quadruplets.

Zachary Klaassen: Yeah. Yep.

Deepak Kilari: But we need to think about scaling back. And that's where I think, "Oh, hopefully we can do a trial where we can look at monotherapy with ARPIs or ARPIs plus five alpha-reductase inhibitors in these older, frail population." And I think there's a quality of life benefit from it. And clearly these patients might not die from prostate cancer. You're treating these asymptomatic prostate cancer patients with drugs that normally with doublets and triplets that cause side effects. So you think you should think backwards instead of say, "Can you find a treatment that has less side effects?"

Zachary Klaassen: Yeah.

Deepak Kilari: So our goal would be to try to move this into a Phase-3 setting or a bigger Phase-2 setting so that providers can sort of look at this data and say, "Maybe I don't need to give everybody ADT and combinations. I maybe should just give ARPIs."

Zachary Klaassen: Yeah.

Deepak Kilari: The biggest question that we all had in the field is what is the added role of ARI? I mean, we didn't really add ARI at progression. We didn't add ARI at a second time point to see what the added benefit is. And we do agree that ARSI's are very effective by themselves.

Zachary Klaassen: Right.

Deepak Kilari: But I still think there might be a role for ARSI's and I don't know how much alpha-reductase inhibitors really added to side effect profile.

Zachary Klaassen: Right. That's great. I think your inclusion criteria with the geriatric assessment is key because you're going to get people that say, "I just don't want ADT."

Deepak Kilari: Yeah.

Zachary Klaassen: But I think this is really highlighting the frailty. Great conversation. Maybe a couple of take home points for our listeners.

Deepak Kilari: So I think geriatric assessments really add a lot to what we see in a patient, or typically when we see patients in clinic, we sort of look at them and sort of say, "They're a fit."

Zachary Klaassen: Yeah.

Deepak Kilari: But if you do a geriatric assessment, you can sort of see how not fit they are. Monotherapy or ARSI monotherapy or ARSI five alpha-reductase inhibitors should be considered an option for vulnerable and frail patients that might not tolerate ADT. And three, there should be bigger studies sort of proving what we just saw in a Phase-2 study to help patients in this population.

Zachary Klaassen: Thanks so much, Deepak. Great conversation. Thanks for your expertise and your time today.

Deepak Kilari: Thanks Zach for having me.

Zachary Klaassen: Thanks.