Zachary Klaassen: Hi, and welcome to UroToday. My name is Zach Klaassen. I'm a urologist in Augusta, Georgia. And I'm delighted to be joined by Dr. Neal Shore, who is a urologist in Myrtle Beach, South Carolina.

Today, we're going to be discussing a case-based discussion, recent advances in real-world decision-making for treating de novo mHSPC. We've seen a lot of activity in mHSPC over the last several years. And so Dr. Shore has been kind enough to walk through a case and discuss some of the implications.

Dr. Shore, good afternoon, good morning. How are you?

Neal Shore: Great, Zach. Pleasure to see you.

Zachary Klaassen: Awesome. So this is a case that I put together. I would like to just present it and then get your thoughts on some of the potential treatment options, because as you know, we have a plethora of options.

And so this gentleman presented to his PCP with back pain, urinary frequency. The PCP drew several key labs. PSA was 39. Creatinine, 2.7, which was his baseline, and slightly anemic with a hemoglobin of 10.

When we look at the rest of his medical history, myocardial infarction, 2011, mitral valve replacement on Coumadin, diabetes, and moderate obesity. His surgical history coincided with coronary artery bypass graft times three in 2011, bilateral knee replacement.

Interesting family history here. Significant for breast cancer. And his sister as other sister had ovarian cancer, former 20-year smoker, married, not sexually active, social wine every evening. And so the PCP sent this gentleman to a urologist and a medical oncologist. The urologist performed a 12-guided TRUS biopsy, 10 cores, Gleason grade group four and 10 out of these cores, and two cores of Gleason grade group five. So certainly high-risk disease.

He gets conventional imaging staging. PSA is 39. CT, abdomen, pelvis with bone scan. Three axial skeletal bone mets, bilateral pelvic lymphadenopathy. And I think to the credit of his oncology team, they recognize this family history. And they did a somatic genetic testing of this biopsy tissue under BRCA1 mutation.

So just for our listeners, to summarize, this patient has de novo, which means he showed up with metastatic hormone-sensitive prostate cancer. He's CHAARTED low volume disease, three axial skeletal mets, some pelvic lymph nodes. He's LATITUDE high risk because he has three or more bone metastases. And he has this high-risk Gleason grade group on his biopsy.

So Neal, he's got plenty of treatment options. And I'd like to just have you walk through some of these options, and maybe pros and cons for both. What is the meaning of a BRCA mutation in metastatic hormone-sensitive prostate cancer, candidacy for chemotherapy, et cetera?

Neal Shore: Yeah, what a great case. We see these patients kudos to his primary care physician for getting a PSA.

Zachary Klaassen: Yeah.

Neal Shore: He had back pain. So many people had back pain. But clearly, in this patient's case, he's got metastatic disease, bone lesions, lymph nodes. And kudos to the team for doing a good family history.

Zachary Klaassen: Yes.

Neal Shore: Significant family history. And then doing the genetic testing. We had a plenary presentation at AUA 2025 this year on the importance of doing a good family history, performing and then getting genetic testing. And lo and behold, the patient's BRCA1, which has clear implications for not only him, ultimately, but also his family members and cascade testing for them picking up breast, ovarian, pancreatic, endometrial cancers early, when they're curable.

So this case is a really, typical case that we'll see. This gentleman has renal insufficiency of a pretty significant amount. I'm sure his GFR is well below 50. Certainly, probably well below 40. Probably does not make him a good candidate for triplet therapy with chemotherapy.

We tend to reserve that more to the high volume. Although there's benefit in the ARASENS population. Certainly, in PEACE-1, we saw more of a benefit for high volume patients. But his renal insufficiency, his performance status really makes him more optimal for doublet therapy. And as you said, we have a plethora of options.

We don't have a PARP approval in the mHSPC space yet. But we have two trials, TALAPRO-3 and the ADDITION trial for niraparib, which I believe will be reporting at ASCO this year. So I think a lot of folks are really interested to see that readout.

You're right. He's low volume disease, on CHAARTED, high-risk disease based upon the LATITUDE criteria. Clearly, he's got aggressive disease. He's grade group 5. Under the con meds issue, back in the day, it used to be everybody was seemingly on Coumadin. We see less of use of Coumadin. He's got a valve replacement. And we see the other anticoagulants that have replaced a lot of the use of Coumadin.

Also, different cardiovascular procedures reducing the risk. The WATCHMAN procedure, in particular. But I think shared decision-making is absolutely the way to go, moving away from being paternalistic. I'm the doctor. I'm going to tell you what you're going to take. And assuming there's good accessibility and cost is not an issue, I think that shared decision-making is incumbent upon the team, the multidisciplinary team, regardless of your specialty to say, OK, your monotherapy is clearly not in your interest. And then review the adverse events of the different ones. And then, of course, access through cost.

Zachary Klaassen: And Neal, I think this gentleman has low volume disease going back to STAMPEDE Arm H. Would you offer this gentleman concomitant radiotherapy to the primary as well?

Neal Shore: Yeah, 100%. Great point. Parker published that from the STAMPEDE Arm H and others as well. I think it's pretty conclusive now that particularly for patients with low-volume disease, absolutely, that they do better.

They clearly do better with progression and survival, but even arguably local control.

Zachary Klaassen: Sure.

Neal Shore: There's a trade off, but I would definitely get the radiation oncologist involved in the decision.

Zachary Klaassen: Absolutely. And then we have this great table from Dr. Mehra's ESMO 2024 for discussion. Just walk through some of the highlights of this doublet therapy. This was after the ARANOTE Plenary presentation.

Neal Shore: Yeah. Niven Mehra put together a very nice table here, looking at the various doublets daro, enza, enza, apa, abi, and abi again here, as you go from left to right. Good number of patients. ENZAMET, and ARCHES, and TITAN had different percentages of docetaxel use.

Age is comparable. The volume distribution is high versus low, also comparable. When you look at the rPFS, they're really fairly consistent in the range of the hazard ratios of 0.5 to 0.4, depending upon how you want to round it off. You see the 0.3 on the STAMPEDE G Arm.

Survival-- we see results don't have them in ARANOTE. Don't know that we will given the crossover that you're going to see. But I think the bottom line is that these were all successful trials. I think it's a good debate regarding the rPFS. We're all always the caveat, be careful about doing cross trial comparisons.

Zachary Klaassen: Yeah, absolutely. Yeah, no doubt. And presenting this, I think you made a good point in the last slide. Looking at all these options, looking at the tolerability side effects, what does this patient looking for? And when we talked about this, he's interested in a tolerable double therapy. You mentioned his comorbidities, not the greatest performance data. So this is where he was going with.

So maybe just walk our listeners through some of the key points from the ARANOTE study.

Neal Shore: Yeah. ARANOTE was presented at last year's 2024 ESMO published in JCO. Very similar trial design to the other mHSPC doublet trials, a 2 to 1 randomization. The stratification, visceral, yes, no, primary endpoint, rPFS, secondary endpoint in all of these doublet trials was a key secondary endpoint was OS. And then the usual other factors.

This was largely exclusively done outside the US. That's a positive successful study. We'll be reporting in the fall, the 200-patient open label ARASEC study. Myself and Rana McKay are the co-PIs on that. And we'll be doing what's called a Match Adjusted Independent Comparator, or a MAIC, M-A-I-C, to the monotherapy CHAARTED arm, which is pretty cool that the FDA approved that trial design.

But here's the bottom line, Zach, is that the KM, the rPFS, hazard ratio of 0.54, highly statistically significant, curve separating early. I don't think this was really a surprise to anybody, but we needed to do this. You got to have the data to show that it works.

Zachary Klaassen: Absolutely.

Neal Shore: Secondary outcome looking at everything to the left favoring darolutamide. Clearly, trending that way in survival. Not yet statistically significant. Time to resistance, time to PSA, progression or PSA, PFS, new subsequent therapies, pain progression, all favoring the doublet which is consistent with doublet over monotherapy.

I think we still see about 35% of patients in the US getting monotherapy. And that number should probably be, in my mind, in my opinion, less than 10%.

Zachary Klaassen: Yeah. No, I totally agree.

Neal Shore: Nothing really new at all on the treatment emergent adverse events, which is really quite a great thing. I think darolutamide reputation for being so well-tolerated, largely because it doesn't cross the blood-brain barrier, at least, in preclinical models.

And if you look at that rectangular red box at the bottom on the treatment emergent adverse events, discontinuation was higher in the control arm than in the therapeutic arm. That should tell you a lot as a clinician in terms of tolerability. And then when you look across all the different factors listed in the bottom box, it's important for the folks who've never used this drug to realize, it is a very well-tolerated therapy.

And there's always some small risks, for sure. Every individual patient has their own empiric finding, but this is a well-tolerated drug.

Zachary Klaassen: Yeah, absolutely. Great discussion of ARANOTE Neal. And I know that the tolerability-- when we say cross trial comparisons, tough to do. We do it. And so when we talk about it on UroToday. But it does factor in, I think, safety and tolerability for somebody who's wanting a good treatment, that's not going to significantly disrupt the apple cart of daily life is important.

So just a couple discussion points, Neal. So going on that side, going on that theme, when you have these discussions with patients, how important is that part of the discussion, side effect profile tolerability?

Neal Shore: Well, I just have to comment. You said the apple cart. But Zach, you're in Georgia. It's peaches, man. It's all about peaches.

Zachary Klaassen: Fair point, Neal.

Neal Shore: And the peach truck.

Zachary Klaassen: That's right.

Neal Shore: Eat a Peach, Allman Brothers. All right. I'm going down a rabbit hole, rock and roll, '80s, '70s. The side effect profile and tolerability, including drug-drug interaction, when so many of our patients on polypharmacy, this patient being on Coumadin, some of the other anticoagulants. We talk about the multidisciplinary team. You got to bring in your pharmacist to help you understand polypharmacy challenges, which would be a cha-- for this patient, I think this is where darolutamide, in particular, has advantages, for sure.

He's got a lot of comorbidities, and, therefore, a lot of concomitant medications. And so for patients who may already have fatigue, who already may have some other concerns regarding cardiovascular challenges, this is a really important aspect of shared decision-making.

And so sometimes people say, well, are you going to just relegate a drug like darolutamide, which is so well tolerated only for those patients? I would say no. I would say it really warrants the full-throated discussion of all the AR pathway drugs and saying, OK, is it a QD, BID, with or without food? What's the lab requirement for monitoring? What about further fatigue issues, cognitive issues? Is this small risk, if you had? What's the incidence? It's not a risk. It's a contraindication, if you've had prior stroke or seizure for some of the other ARPIs?

Zachary Klaassen: Yeah. No. Great discussion. In your opinion, we've laid out one case, but just for our listeners, who's the ideal candidate for doublet therapy with darolutamide plus ADT?

Neal Shore: Well, I think the data is conclusive, at least from the ARANOTE study. And kudos to all the investigators who did this during difficult times, really starting during COVID. I think it's really anyone who's either de novo or recurrent. So synchronous, metachronous, low volume, or high volume, who does not want to have triplet therapy. I offer it to all of those patients.

Zachary Klaassen: No, I think that's accurate. And, again, in ARANOTE, there was, I think, roughly one-third of the patients were recurrent as well. So those patients that have had therapy, and then they see the metastasis down the road. We've talked about shared decision-making, but I think it's important to wrap it up with this discussion. In your opinion, what are the important aspects in that discussion? What are you really highlighting?

Neal Shore: Well, first, again, love that this patient had a good family history, love that genetic testing was performed. I, for one, strongly believe that germline genetic testing should be democratized, should be universal for all prostate cancer patients, regardless of their grade group, because there's inter-observer variability. And many patients just don't know their family history.

If we could get cost to not be an issue, which it's not in the US, it can be in other countries. So I'm sensitive to that. The downstream cascade family importance is huge. And part of that shared decision-making process is a good family history, and doing all the right testing, other than just doing a CBC, a CMP, and a PSA.

But I think that for these patients, the other next really important point is monotherapy should only be relegated to a very small percentage of patients, who are very frail, who maybe have just so many other comorbidities. But even with that, I usually can start off with lower dosing than the approved label dose, if there's a lot of anxiety about additional side effects, and then work my way back up.

I always think that darolutamide, for example, is 600-milligram dose BID based upon ARAMIS and ARASENS. And now, we have ARANOTE. But for some patients, if they're very anxious, I may start them on 300-milligram BID, just to give them some tolerability, follow-up within a month. That to me is part of the art of decision-making and the shared decision methodology.

Zachary Klaassen: Yeah. I like the fact you brought up starting lower, because we can do half dose, especially in those patients with severe renal impairment. This patient's probably on that borderline of severe renal impairment.

But I think for tolerability, that's absolutely a great point. Neal, always fun chatting with you about advanced prostate cancer. Anything we didn't touch on you want to tell our listeners.

Neal Shore: Well, this was a great case because it's so instructive in so many ways. I believe in checking a PSA, doing it thoughtfully. Regardless of age, family history, incredibly important, genetic testing, incredibly important. If the patient has mHSPC, low or high volume, de novo or recurrent, exploring all of the options for them.

And we do have this plethora or, oftentimes, called an embarrassment of riches. And I think it's important for patients to understand they have choice.

Zachary Klaassen: Yeah, absolutely. Neal, always appreciate you taking time out of your busy day for UroToday. Thanks again.

Neal Shore: Pleasure. Thanks, Zach.