Neeraj Agarwal: Welcome to UroToday. Today, we have our esteemed guest, Dr. Zach Klaassen, urologist and associate professor in urology in Medical College of Georgia. Zach, thank you for joining us today.

Zachary Klaassen: Neeraj, always great chatting with you. I enjoy our discussions on UroToday.

Neeraj Agarwal: So today we'll be discussing the recent advances and real-world decision-making for treating patients with metachronous metastatic hormone-sensitive prostate cancer. So let's get to the case.

This is a 80-year-old White man with a history of Gleason grade 3 prostate cancer treated in 2015, 10 years ago, which was treated with external beam radiation therapy plus six months of leuprolide. Here we can see the PSA trend. PSA has been slowly rising after completion of radiation therapy and ADT. And now in 2025, PSA is 17.5 nanograms per mL.

The medical history is remarkable in this 80-year-old man, for myocardial infarction three years ago in 2022, which required three cardiac stents placement. And patient is currently on Plavix. Patient also has hypertension, hyperlipidemia, obesity and ECOG performance status of 2.

Surgical history is remarkable for cardiac catheterization, as we mentioned, and a hip replacement surgery. Family history is important for brother with prostate cancer, who is alive, fortunately, and has no evidence of disease.

From the social history perspective, patient is married, a retired engineer, a former smoker with a 10-pack history, and a social alcohol use. So very typical elderly patient we see in many of our clinics.

Patient underwent a PSMA PET scan because of PSA recurrence, and it shows intensive uptake on the left side of the prostate, bilateral pelvic lymph node enlargement, and two bone metastases, both in T8 and T10 vertebrae.

Patient declines any further biopsy. But based on PSMA PET scan, it is quite obvious that patient has what we call as metachronous or recurrent metastatic hormone-sensitive prostate cancer. And from the volume perspective, patient has a CHAARTED low volume disease. So Zach, what treatment options does he have in your clinic?

Zachary Klaassen: Yeah. As you mentioned, Neeraj, this is a very typical patient. They were treated several years ago. They've had prostate cancer for a decade. Unfortunately had a little bit of loss of follow-up. This is the importance of still checking that PSA at least annually. And unfortunately presents with a PSA of 17, gets the appropriate staging.

And so again, he has metachronous low volume metastatic hormone-sensitive prostate cancer. In the last decade, Neeraj, we have a plethora of options for this patient. And I think if you look at what's summarized here, we have triplet therapy, which has been based on the ARASENS trial. Darolutamide plus docetaxel plus ADT.

And we have a host of doublet therapies in terms of ADT plus either enzalutamide, apalutamide, darolutamide or abiraterone. So the question is not if we're going to treat them, it's and how intensive we're going to treat this patient.

Remember, 80 years old, several comorbidities. I think in this patient with the comorbidity profile, the performance status, recurrent low volume metachronous metastatic hormone-sensitive disease, I don't think triplet therapy is an option for this patient.

So I'm really looking at one of the doublets in this situation. And so after going through all of these options-- again, we've highlighted here shared decision making is very crucial. What are the patient's goals? What does the family have to say? What are your thoughts as the clinician in terms of guiding these things?

We talked about not necessarily pursuing triplet for this patient. But then really delving down to side effect profiles, what's going to affect the impact of the quality of life based on what we decide to do? So based off of that-- now, the patient's very interested in darolutamide plus ADT as a doublet therapy.

I think a couple of points perhaps on that sort of doublet therapy side discussion is that we know that they all work. We know that they work very, very well. So you're really looking at that point at several other factors in terms of what may be better tolerated in this elderly patient versus some of the other options. And so going through that discussion, he's interested in this doublet of darolutamide plus ADT.

Neeraj Agarwal: These are very good points. Obviously patient has low volume disease. Elderly patient with multiple comorbidities. So I agree, docetaxel is likely not the best option for the patient. And also, we have never seen ADT plus ARPI at doublet being trumped by ADT plus docetaxel plus ARPI.

So based on those two factors, I fully agree with you that a doublet therapy is the most appropriate option for this patient with metachronous low volume hormone-sensitive prostate cancer. I agree with shared decision making. So how did you arrive at the decision to start ADT plus darolutamide? I'm interested in knowing the decision making process.

Zachary Klaassen: Yeah. And I think-- when we look at these, obviously we have things as a clinician that-- how we propose it to the patient is going to be important. Because we do have, in the back of our mind, what we ultimately are thinking along those lines. So I think to answer that question, I'll go through how this data came about with darolutamide plus ADT.

As our listeners know, ARANOTE was presented first at ESMO in 2024. And this is the fourth sort of doublet therapy ARPI plus ADT in this disease space. And this was a global randomized, double-blind, placebo-controlled phase III study.

The placebo-controlled ADT arm was deemed not standard of care in the United States because we should be treatment intensifying. But in a lot of other areas of the world, their access to double therapy may not be quite as accessible as in the US.

So this was an ex-US study. Randomization, two to one, darolutamide plus ADT versus placebo plus ADT. Classic patients metastatic hormone-sensitive, ECOG of zero to two. This patient is ECOG 2. So on the upper end of the performance status.

And you can see the stratification factors listed here. And the endpoint here was radiographic progression-free survival, key secondary endpoints overall survival, and time to initiation of subsequent anti-cancer therapy, time to mCRPC.

So we heard about this first trial readout in ESMO 2024. For the purpose of our discussion, this is a low volume metachronous recurrent patient. And in this study, 17.9% of patients were recurrent, 29.5% were low volume.

So this is what was presented by Dr. Fred Saad at ESMO. This is the intention-to-treat population, showing a significant reduction in the risk of radiographic progression or death by 46% for darolutamide plus ADT versus placebo plus ADT.

So a positive trial based on the primary endpoint being reached. Now, what's interesting for our discussion-- again, this is a low volume patient. There was about 30% of patients, as we mentioned, that were low volume. And then what was presented at GU ASCO just recently in 2025 was some of these breakdowns of high volume and low volume.

And I've basically put together some of these curves, highlighting that low volume population. And we see in these patients, again, a benefit to darolutamide plus ADT. Important to note, all of these are not powered to show a difference, but we do them as post-hoc analysis from these trials.

So improvement in radiographic progression free survival, also improvement in time to mCRPC. And this is an important point. I like this endpoint for patients because this is the question of Doc, how long is this going to work for me? How long till my disease progresses? How long till I need another treatment other than what I'm on at the current time?

So I think these are two important endpoints. This is a very key secondary endpoint of time to mCRPC. Again, not powered to show a difference, but we do see hazard ratio of 0.21, favoring darolutamide plus ADT.

A couple of other important volume-specific aspects that were presented at ASCO GU in 2025, this concept of undetectable PSA. I think this is a very important concept for our listeners, for patients.

We are trying to get this PSA as low as possible as quickly as possible. We're not trying to get from 15 to three. We're trying to get from 15 to less than 0.2. And even most recently, presented by Neal Shore, AUA less than 0.02 is even better than less than 0.2.

So this was presented looking at how long it took to get to 0.2 for these patients. You can see here, 24 weeks from starting of treatment, we see a 72% versus 17%. Up to 48 weeks, 79% in the combo arm versus placebo. And ADT, 19%.

Any time during the follow up we see that darolutamide plus ADT got the PSA less than 0.2, 83% of patients versus 25% in the placebo plus ADT.

So I think we know that this leads to a discussion of this is working for the patient, and hopefully we can stay on the treatment as long as possible.

Obviously, this is an 80-year-old man. We've talked about him. Somewhat comorbid obesity, ECOG performance status of two. And so how this tolerability is going to affect his life is really important. I think I've highlighted here, low volume, very similar to the intention to treat population in terms of side effects.

We see grade three, four adverse events about one in three patients. Very similar to the overall population. And what I'd like to also point out, in the intention to treat population, fatigue was actually a little bit less in the darolutamide plus ADT arm compared to the placebo plus ADT arm.

So I think tolerability for this elderly patient-- low volume disease, we've seen the efficacy data now. I think this is the reason that we led to this discussion of darolutamide plus ADT for this patient.

Neeraj Agarwal: Great point, Zach. And I'm so glad you presented the recent advances in patients with metastatic hormone-sensitive prostate cancer. And our ARANOTE trial is one of the major advances which happened in the last one year. So thank you for presenting those data. Definitely very useful to our viewers.

Just going back to the previous discussion, what are your thoughts on adding chemotherapy? Just for the sake of discussion. I'm sure one of the patient's sons or daughters may have asked, like, Dr., we have heard about chemotherapy being added to the doublet. So what are your thoughts? How do you explain not using chemotherapy in this patient?

Zachary Klaassen: Yeah. I think we talked about it in that vast options that we have. I think there are certain patients that will definitely benefit from chemotherapy intensification. And that's a patient that comes in a high volume disease, young patient, active, where we're really trying to hit this tumor three different directions with ADT, darolutamide and docetaxel.

And I think in this patient, that's probably not the case. This is a more elderly patient, low volume disease. We have other options that are better tolerated that work very, very well. And so I think that's what this comes down to.

When we're presenting the options to the patient, we can say, yes, this is an option. We can give chemotherapy. But based on a sample size of one, 80 years old, several comorbidities, I don't think that's the best option for a low volume recurrent elderly comorbid patient.

Neeraj Agarwal: I agree. I would do the same. I will not offer chemotherapy to this patient. So how much does the side effect profile and tolerability fit into your busy urology clinic in your decision making for metachronous mHSPC treatment, not only for this patient, but other patients as well?

Zachary Klaassen: Yeah. Absolutely. I think as we mentioned, we have all these options that work very well. So I think that-- a shout out to just treatment intensification in general. And I think that's important is that ADT monotherapy, for the majority of patients, is insufficient in these situations in 2025.

And so we start to look at things like the drug-drug interactions. Certainly cost and payer coverage are all going to make a big difference. And there's little nuances to perhaps one treatment may be favoring slightly compared to the others. And again, we have to remember that this has not been compared head to head. We compare them head to head when we have these discussions and in the clinic. But part of it is experience with the agent, having a little bit of gestalt and based on how the patient looks in front of you, and maybe choosing one versus the other. But it is a very-- the art of medicine, so to speak, when we're selecting these based on tolerability and safety.

Neeraj Agarwal: So again, this is an important aspect of what we do in the clinic. Can you speak to the importance of shared decision making in this disease space, and specifically for this elderly patients with a lot of comorbidities?

Zachary Klaassen: Yeah. This is key to all of our discussions, isn't it, Neeraj? We do this every single day in the clinic, and I think it becomes part of our conversation. For the most part, we have whether it's a spouse, or a daughter, or a son, or a relative, a neighbor, somebody bringing the patient to the clinic, they're going to join these patients in the clinic.

And it's really a conversation between the physician, the patient and the family member or the caregiver that's with the patient. The importance of this is that because when there's so many options, there's not necessarily one right option. There may be a better option or a less better option, but there's options that have to be weighed against each other.

They're relying on us as the quote unquote "experts" to tell them what the options are, what our thoughts are, but also being very honest about side effect profiles, whether-- maybe overtreatment.

We talked about chemotherapy maybe not being appropriate for this patient. But it becomes, what's the goals of the patient, what are their goals in terms of avoiding toxicity, living as long as they can? All of these things come into that conversation.

We have to take that as a key player in the conversation, but also being cognizant of what our recommendations are for them as well. So it's absolutely vital not just in all patients, but particularly in somebody like we're talking about here, 80 years old, a little bit on the comorbid side.

Neeraj Agarwal: Personalizing medicine on a day-to-day basis with shared decision making.

Zachary Klaassen: Everybody's a sample size of one in your clinic.

Neeraj Agarwal: Yes. I love it. So any take-home message before we conclude?

Zachary Klaassen: Yeah. Thanks so much for having me, Neeraj. I think we've got such a plethora of options in metastatic hormone-sensitive prostate cancer. We know that roughly 15% to 25% of patients will fall into this recurrent or metachronous metastatic hormone-sensitive prostate cancer.

And particularly in these patients that are maybe a little bit elderly and comorbid, really sit down and look at the options with the patient and their family. It's really important. We know that they work so that that discussion also has to translate into what's the patient going to expect, how is it going to impact their quality of life?

We really have to do our job and lay out the options, be honest with the patient, really focus on quality of life, particularly in our elderly patients and comorbid patients. We want to do what's right for them, but there's also an aspect of the clinical art of medicine. I think this is something that comes with experience and comes with using these agents.

Again, another shout out for treatment intensification. We know that not just in our country but across the globe, treatment intensification still is lacking. So we have to do better. We have many options, but we have to use them.

Neeraj Agarwal: Thanks, Zach for sharing your experience and expertise here.

Zachary Klaassen: Thanks so much for having me, Neeraj. Always great chatting with you on your UroToday.