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Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I'm delighted to be joined on show UroToday by Dr. Jason Hafron, who is a urologist at the Michigan Institute of Urology. Today, we're going to be discussing a case-based discussion looking at recent advances and real-world decision-making for the treatment of metachronous metastatic hormone-sensitive prostate cancer. Jason, thanks, as always, for taking time out of your busy day to join us.

Jason Hafron: Yeah, thank you. Really a pleasure and honor to be here on UroToday with you, Zach.

Zachary Klaassen: Awesome. So I'm going to just tee up a case for you, Jason. I think this is something we see not infrequently, regardless of where we practice in the country. So this is a 52-year-old healthy gentleman presented to his urologist for a follow up PSA. Three years ago, at the age of 49, he had a robotic prostatectomy, pelvic lymph node dissection, followed by early salvage radiotherapy.

And if we dig a little bit deeper into his history, to 2022, he has a screening PSA, again at 49. PSA is 11. He has a TRUS biopsy. 4 cores of Gleason grade group 3 prostate cancer, then undergoes his surgery, pT3 R0N0, 15 nodes negative, M0 Gleason grade group 4 in 35% of his prostate. His urologist then does somatic, as well as germline testing, and he's found to be BRCA2.

He has quarterly PSA post-operatively undetectable at first, but then shortly thereafter, we start to see a signal. He undergoes appropriate salvage radiotherapy. His PSA is undetectable after salvage radiotherapy, but he's lost to follow-up for about 18 months. He had a job switch. Had a health insurance gap. And then he represents to us three years after surgery. PSA is up to 3.9.

So just to lay a little more of the groundwork for this gentleman, relatively healthy hypertension and erectile dysfunction after his prostatectomy, his surgical history you can see here is prostatectomy. And then did have a penile prosthesis placed. He has a strong family history. I think one of the take-home points from this case is always get a good family history. Young guy, uncle, prostate cancer; mom, breast cancer; sister, ovarian cancer. So the urologist here was really on the ball with seeing that pathway, getting that germline and somatic testing, finding that BRCA2.

He's a healthy guy, insurance broker, married for 15 years, has two teenage children, sexually active after his surgery for the penile prosthesis. 10 pack year former smoker, social alcohol. So when we look at this guy, he comes to our clinic. Obviously, he needs restaging. So he presents to the clinic after this gap in his care. He's got a PSA, a PET scan that shows two para-aortic lymph nodes and a T10 1-centimeter metastases.

So this gentleman, what does he have at this point in time? He's metachronous. So he's had recurrent metastatic hormone-sensitive prostate cancer. CHAARTED low volume. I know this is delving a little bit into CHAARTED being conventional imaging. PSMA PET, obviously what we're using these days. But he's a low-volume mHSPC. So this gentleman's got lots of options, Jason. So I want you to run through this with our listeners. And I've pulled this slide from an ESMO discussion by Dr. Mehra just to help set the landscape for all the options this guy does have.

Jason Hafron: Yeah. Thanks. Great presentation. And unfortunately, this is a case we see on a regular basis all across the country is a failure of surgical therapy, failure of salvage radiotherapy now with this oligoprogressive disease. And Zach, I agree. We have many options today. And this is a nice summary table of all the major trials for doublet therapy that are available.

And as you can see, most of these trials were very large trials. They are pretty typical or demonstrate consistent with what we're treating today. And as you look as the overall or the progression-free survival is they all have great responses. Hazard ratios ranging from 0.29 up to 0.54. So very, very effective therapies. And I think we can say across the board, with all of these ARPIs, we have a lot of options. And we're spoiled right now.

Zachary Klaassen: Yeah.

Jason Hafron: And I think the key is that, as you are deciding and talking to this patient going through your shared decision-making, there are differences. And I think what we want to highlight today is some of those differences, specifically the differences related to the ARANOTE study or darolutamide. And I think in this discussion, one of the things that stands out or one of the options is darolutamide, but one of the differences is it's more tolerable, and just as efficacious as the other therapy.

So here the summary slide shows similar efficacy across the board. But when you look at the ARANOTE trial, which was recently completed, we see differences. Here's the trial design. Pretty standard trial design for all these drugs and doublet therapy. mHSPC was required. ECOG 0 to 2.

You see the pre-stratification factors. 2 to 1 randomization darolutamide, 600 milligrams BID plus ADT versus placebo plus ADT. Primary endpoint was rPFS. You can see the secondary endpoints. So standard trial, all of the trials pretty much followed the same skeleton or design. But I think when you look at the results, you start to see differences between these therapies.

Here's the primary endpoint-- progression-free survival, the proverbial home-run slide that we always like to refer to it. But the bottom line here is darolutamide significantly reduced the risk of radiographic progression by 46%. So we see excellent results. We're seeing the trial, ARANOTE, hit its primary endpoint with a very strong hazard ratio. So clearly, a very effective agent to be used in this patient.

But here I will say this is probably the home-run slide not using our Kaplan-Meier curve. This is where we see differences. I think this is where as urologists we need to understand the nuances of these drugs, which is evident in ARANOTE trial. And it's specifically the TEAEs or the Treatment Emergent Adverse Events is these drugs are not all the same. And when you look at ARANOTE, you look at the TEAEs or the adverse events, the discontinuation rate, if you look up on the top left, was 6.1% versus 9% in the placebo arm.

So the adverse events were less in the treatment group versus the placebo group, highlighting the safety of this drug, highlighting the tolerability of this drug is that we are seeing less AEs in the treatment arm with the use of darolutamide compared to the placebo arm. When you dig deeper and you look at that bottom right panel, I think the one that stands out to me, as a practicing urologist is fatigue.

Look at the incidence of fatigue, Zach. It's 5.6% in the darolutamide arm versus 8.1% in the placebo arm. When you compare, we're not supposed to do it, but we always do it, these are very low numbers. But what is very appealing is that darolutamide has less fatigue than the placebo arm. You look at falls and bone fracture, very low rates.

So we've shown that it's efficacious now as this-- we're seeing that there is a difference that this drug appears to be more tolerable, has less discontinuation rate, less fatigue, less falls and fractures than we have historically seen with the other therapies. So when I talk to patients about the options and we run through what we can do, I think it's important as a urologist to explain the value or highlight the differences that darolutamide offers these patients.

And another thing, and this is very particular to the case is low volume. This guy was low-volume disease. He was oligoprogressive. He failed therapies. Is that, look at this hazard ratio. I don't know if you were impressed with this, Zach, but that hazard ratio is amazing-- 0.3 for rPFS when they broke it down and did subset analysis. So in that case, in this guy's case where he has low-volume disease or metachronous progression, this seems like the ideal option for this patient who's also very young.

I think that's important, too, because going back to the previous slide, you want to minimize his-- you want to maintain a high quality of life. He's still working. So why not choose an option that has less side effects and has very efficacious data based on the ARANOTE.

And then the other thing is, time to mCRPC, this was one of the secondary endpoints. Here you clearly see a very strong hazard ratio here, a very strong signal showing that you can delay mCRPC significantly. And we know that, mCRPC is lethal and can lead to worsening outcomes. So clearly, based on ARANOTE and the subset analysis of this, darolutamide appears to be a great option for this young gentleman with low-volume disease.

And here's another concept that I think is interesting. When we first started talking about advanced prostate cancer, we used to tell urologists, my partners, don't worry about the PSA, don't worry about the PSA. But we've changed gears here a little bit, and ARANOTE highlights the importance of the PSA or the prognostic value of PSA.

And what you see here is that 83% of the patients with low volume, the case we're presenting today, had an undetectable PSA. Even though we don't tell patients, we tell our patients not to worry about the PSA, we tell our partners not to worry about the PSA, but we all like to see an undetectable PSA. It makes us sleep better at night. It reassures us that the patient's doing fine. And in ARANOTE, in patients with low-volume disease, you see an 83% undetectable PSA.

And then this is some further breakdown that Fred Saad did recently presented, which I think is important for multiple reasons. When you look at PSA response less than 0.2 or undetectable PSA, the baseline PSA matters. And in our case, the guy's PSA was 3.9. Here in less than 4.9. His any time response to undetectable PSA is 88.

But if you wait till his PSA gets up to 4 or 21 or even beyond 21, you see that his response rate to undetectable PSA goes down. And I think this is important information. Not that we got to get lost in the numbers, but I think as urologists, as practicing clinicians, this tells us that we can't wait. You don't want to sit on this patient. You want to treat them earlier, and earlier is always better.

OK. And we've seen this in iterations through multiple trials. But here ARANOTE documents that waiting or watching the PSA is not good. That you want to jump on them. Switch right away to doublet therapy because if you switch early or you add doublet therapy early, the patient will have a better response.

And also, I just said that we don't worry about PSA, but we do, and we like to see it. I've been using-- I don't know about you, Zach, in your clinic-- but when you see that undetectable PSA, whatever time period you use at three or six months, I think that's very helpful in guiding these patients for future therapies and how I interact with that patient. When I see that three or six month PSA go to undetectable, my conversation is different. I'm reassured. I reassure the patient that we are probably going to get a very durable response, and the patient is going to be doing well for many years.

Zachary Klaassen: Yeah.

Jason Hafron: When I don't get that undetectable PSA, my conversation is different because I know that that patient's going to fail early. They'll still respond. I'm not stopping therapy. But I have to start preparing them for an early failure and start to think the next line of therapy that I'm going to offer that patient.

And we know, Zach, that there's multiple trials going on to look, is this a point? We don't know now. The data is not out. Studies are being done. But is this a point where to intensify therapies and add additional layers of therapy? We don't have data to support that. But I think what we know today is that early PSA, when it becomes undetectable, is a very important milestone in the path that that patient's going to go through for the next couple of years.

Zachary Klaassen: Yeah, absolutely. Jason, I think one of those trials that I'm excited about in that context is the TRIPLE-SWITCH trial, where we're going to start off with doublet. And then we're going to see at that 6 to 12-month window if their PSA is undetectable. If it is, fantastic. If it's not, they're going to get randomized to continuing with the doublet versus layering on docetaxel.

So I think we're going to get a lot more nuance in how we have a doublet background perhaps incorporating that triple therapy if they don't have a good PSA response. So that'll be probably out in a couple of years. But certainly, we've seen that trial in progress a couple times in the last 6 to 12 months as well. So great discussion, Jason. I just want to wrap it up with a couple of discussion points. Just to bring everything together, we've had a case here that we both mentioned we see not infrequently. Who in your opinion is that perfect patient for the doublet darolutamide plus ADT?

Jason Hafron: I think it's really all comers. I mean, I think every patient can tolerate this. We know the tolerability is excellent. And based on the trial design, which we didn't talk about, is they took elderly patients. There was a significant population of, I think, it was plus 85-year-olds. Very diverse population-- so high Asian, Black. So we know based on the trial that they did that darolutamide is an option really for everybody. There's no one that you can't use it on really that I see based on the way ARANOTE was designed.

Zachary Klaassen: Yeah, and I think you mentioned it there. The generalizability of this trial just seems to be a little more than some of the other ones we've seen in the last few years in this disease space. So you're absolutely right. I think 30% metachronous, 70% de novo. That was the higher number of metachronous than maybe some other trials. So absolutely, I think this is at least a conversation with everybody coming in, whether they're low volume, high volume.

One thing I want to get into, I know you guys do a great job at your place of doing genetic testing. I think I'm going to make two parts out of this question, really. How do you implement cascade testing in this patient who has two teenage sons, but also how do you take the information at the time of the metachronous metastatic hormone-sensitive prostate cancer state? And how do you use that BRCA2 mutation for future conversations, assuming that he'll hopefully get a good run out of the darolutamide plus ADT?

Jason Hafron: Yeah, I think first we have to talk about the importance of testing.

Zachary Klaassen: Yeah.

Jason Hafron: Unfortunately we're not seeing great testing rates through urologists across the country. As urologists, as champions of prostate cancer, as the leaders of this disease, we need to test more and test better. The rates are embarrassing. And we really work at it at our group. We're trying to get over 90% testing rate. So it's very important, especially as you see in this case, the identification, the early identification of a homologous recombinant mutation is critical. And we see what happens to these patients. These patients fail therapy after therapy. They don't do well. We need to identify these patients so that we can intensify therapy.

I think you were alluding to it, Zach. Right now, the option based on current approvals is doublet therapy. But in the future, maybe a PARP in the CSPC space would be a good option or consideration, but not right today. But I think the key is that as urologists we have to test these patients. It's our duty and responsibility to identify these mutations, and we need to do a better job.

As far as cascade testing, cascade testing is when you find these positive mutations that you are responsible to the patients responsible. And we have a responsibility to the patient's family members to get them tested. In our practice, we do a lot of testing, but all positives-- and all VUSs within notable mutations-- we refer to the genetic counselors. It's the responsibility of the genetic counselors to do the cascade testing, bring in the family members, discuss their risks. We don't really get involved with it.

But it's like, if you find a lung mass on a chest X-ray, you're not going to manage that lung mass. If you find a BRCA2 positive test, you're not going to manage that. That patient has to be referred to the specialist. The specialists are experts in managing that patient, risk as well as all their family members.

Zachary Klaassen: Yeah, absolutely. That's a great answer. Lastly, when discussing darolutamide as part of the treatment intensification for metastatic hormone-sensitive prostate cancer, and you alluded to this a little bit, to what degree is PSA response part of that conversation. Maybe just bring it together for our listeners.

Jason Hafron: I think PSA response is becoming a more and more important factor or point in the patient's disease journey.

Zachary Klaassen: Yeah.

Jason Hafron: I think when they don't respond, that's worrisome. And when they do respond, it's great. And I think it affects how you talk to these people, how intensely you follow these patients. But what you were talking about is that this point may be a juncture, even though they're not technically failure, where we would add intensification, switch them to triplet therapy, layer in docetaxel. But I think the key is that, as urologists, we need to start looking at this and incorporating this into our practice because there's definitely more to come on this.

Zachary Klaassen: Sure. Jason, absolutely a high-level discussion. Any take-home points, anything we haven't hit on in this 15-minute conversation?

Jason Hafron: No, it was great discussion. Always a pleasure to get together with you, Zach. Today brings so much great education, such a great resource for all of us.

Zachary Klaassen: Thanks, Jason. Always good chatting with you as well.