Zachary Klaassen: Hi. My name is Zach Klaassen. I'm a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. Delighted to be joined by a close friend of UroToday, Dr. Neeraj Agarwal, who's a Medical Oncologist at the Huntsman Cancer Institute in Salt Lake City, Utah. Thanks so much for joining us, Neeraj.

Neeraj Agarwal: Thanks for having me, Zach. Always good to see you.

Zachary Klaassen: Always good to see you too. We're going to have a case-based discussion today, looking at recent advances in real world decision-making for the treatment of de novo metastatic hormone-sensitive prostate cancer. So I put together this case. I'll lay it out for you and our listeners. This is a 67-year-old African-American male presented to his primary care doctor with left hip pain and some urinary hesitancy.

So very general symptoms. Some key labs at that point were notable for a PSA of 108. His creatinine was up a little bit from his baseline of 2.1 at 2.4. Hemoglobin of 11. And so when we look at this patient on a whole, relatively healthy. Hypertension, hyperlipidemia, diabetes. Is on a apixaban for AFib.

He has some PTSD from his time in the US military. He does have some hardness of hearing as well. Surgical history, relatively unremarkable, inguinal hernia repair. Does have a relatively strong family history of prostate cancer. Paternal uncle and father both treated, both doing well. As I mentioned, US veteran, former smoker, married, sexually active, social alcohol, quite vibrant, 67-year-old, although with a few comorbidities as listed here.

So at this point in time, he's referred by his PCP to urology for a biopsy as well as medical oncology. He has a 12 core guided TRUS biopsy, 8 cores of Gleason grade group 5, 2 cores of Gleason grade group 4. Again, PSA 108. He has a CT bone scan at that point. 10 axial skeletal bone mets, extensive pelvic lymphadenopathy. He does have somatic genetic testing with no actionable mutations.

And so I think it's important at this point just to take a pause and just highlight what this patient has. At this point, he has de novo, which means he showed up with metastatic hormone-sensitive prostate cancer. Based on the CHAARTED volume criteria, is high volume, and based on the LATITUDE risk criteria, he's high risk. So what treatment options does he have? And I will look at the next slide, and have you walked through some of the aspects that may guide your treatment for this patient, Dr. Agarwal?

Neeraj Agarwal: Thank you very much for presenting this case. Very representative of what we see on a day-to-day basis. So let's talk about the candidacy for chemotherapy in this case. We'll just look at the guidelines. High volume disease, high risk disease. So seems to be a candidate from that perspective, but then you start diving into the past medical history with the long-term diabetes, for example, and a high creatinine.

That tells me that it's likely that the blood sugar was not very well-controlled. And kidneys have taken the brunt of that diabetes, probably has underlying nephropathy. It is also highly likely that the patient also has baseline neuropathy, even though he is not reporting any symptoms of neuropathy, but is very likely, just looking at the long term diabetes and the effect on the creatinine.

So from that-- and patient has other comorbidities, not too severe, but does have atrial fibrillation and is on chemotherapy. Is on anticoagulation for that. So based on that and the fact that ADT plus ARPI, doublet therapies are quite strong, quite potent therapeutic options. And they have never been compared head to head with triplet therapies, so ADT plus ARPI plus docetaxel chemotherapy.

So we cannot really say ADT plus ARPI is an inferior therapy to chemotherapy in any volume disease. So coming back to the question, I think patient is likely not a chemotherapy candidate in my perspective or not a strong chemotherapy candidate. And I would like to go without chemotherapy in this patient, and will offer ADT plus ARPI.

Zachary Klaassen: Absolutely. And I think just to take this all together, there's a lot of options. All of these work very well. It's looking at the patient, talking to the patient and their family. This buzzword we have these days. This is all shared decision-making, isn't it?

Neeraj Agarwal: Absolutely. I will definitely bring up the data regarding triplet chemotherapy or triplet regimens. Doublet regimens. Definitely talks about pros and cons. And ultimately, in my clinic, patients make the decision.

Zachary Klaassen: Yeah. Absolutely.

Neeraj Agarwal: We help them make the decision.

Zachary Klaassen: That's right. So I've taken this beautiful table from some of our UroToday coverage from ESMO 2024 by Dr. Mehra. It's a great side by side. Of course, we can't compare trials. We use it as our caveat. But just looking at this data, what is important for our listeners to take home from this table?

Neeraj Agarwal: I'm so glad. You brought up the point that these trials have not been compared with each other. And we see a consistent theme here that all combinations seem to be very effective and life-prolonging. Most of them. So if you look at LATITUDE, TITAN, ARCHES, ENZAMET, obviously, these are older trials. So they have more mature data. But all of these combinations in front of you right now, we are seeing quite strong benefit in terms of progression-free survival. And most of them had quite strong overall survival results, both in high volume and low volume disease patients.

So my take on this table without getting into the nuances of each one of those trials for our viewers, ADT plus ARPI combination is a very effective combination strategy for our patients with newly diagnosed metastatic hormone-sensitive prostate cancer.

Zachary Klaassen: Yeah. Great take home message. And I think the key here also is, treatment intensification, whatever you choose is better than ADT alone. And that's what these trials have all showed us as well.

Neeraj Agarwal: I'm glad you brought this up. Just a very quick note. We'll be lucky to have doublets applied to most of our patients. Right now even that is not happening. So I'm so glad you mentioned ADT monotherapy, which is still being used in a pretty substantial number of patients out there in the community.

So my take on this table is, I want to tell our viewers, audience that we have such strong regimen of ADT plus ARPI, which is apalutamide, abiraterone, enzalutamide, darolutamide. Let's try to use them as much as possible, rather than using single agent ADT monotherapy, which is clearly unacceptable in today's times.

Zachary Klaassen: Yeah. That's well said. So for the remainder of our discussion, I just want to walk through some points, maybe related to this case, maybe just in general. For this patient, I think you alluded to it. Is there any specific regimen you would treat versus another one?

Neeraj Agarwal: So as I said, I will lean towards an ADT plus ARPI. Patient has likely baseline because of long standing diabetes and nephropathy. Patient likely has neuropathy. Elderly patient, other comorbidities. So I would lean towards a regimen without chemotherapy in this patient. So ADT plus ARPI. And then we should start dissecting the word-- further dissecting the data from different ADT plus ARPI regimens.

So if we look at abiraterone, for example, multiple studies have shown, both real world and the STOPCAP M1 results recently presented in ASCO GU that for older patients, although they focused on 75-year-old plus, our patients seem to be on the-- he's 67, but has other comorbidities. Hypertension, especially diabetes. I will not be very enthusiastic about using abiraterone in this patient for these reasons.

Atrial fibrillation, so has cardiovascular morbidities which are quite significant. So then let's move to the AR blockers. Potent androgen receptor blockers. And we have three options here. Apalutamide, enzalutamide, and darolutamide. Historically, we have used darolutamide in the context of triplet chemotherapy based on ARASENS trial, but now we have darolutamide available through the ARANOTE study recently presented data in the last one year. And we are focusing on recent advances here.

So that is definitely one of the options. And then apalutamide and enzalutamide are used in the community for almost five years now in this setting. So I would lean towards a direct potent androgen receptor blocker in this patient over abiraterone, as far as ADT plus ARPI doublet is concerned.

Zachary Klaassen: Wonderful. And looking at our second question. How much does the side effect profile and tolerability fit into your discussion when you're deciding what treatment to give these patients?

Neeraj Agarwal: Absolutely. So I'm assuming here we'll be talking about concurrent medications, drug interactions in a moment. But again, the side effect profile is very important, especially in the context of neuropathy, which is highly suspected, even though this is not a diagnosis, which is mentioned in the past medical history.

But we are all experienced clinicians. We think about those possibilities in patients with long-term diabetes. So tolerability perspective, I would be again, cautious of chemotherapy. I would be concerned about using chemotherapy in this patient, because docetaxel can definitely make neuropathy worse.

Again, patient already has hearing loss. Some component of neuropathy looks like. And then definitely at a high risk of fall based on all these. So it's possible that chemotherapy can make it worse. Abiraterone, I would not lean towards abiraterone because of cardiovascular issues. Abiraterone is known to cause worsening of hypotension. Patient already has hypotension. Atrial fibrillation. So from that perspective, I would probably not be very enthusiastic about abiraterone.

So we are down to three ARPIs. Androgen receptor blockers. Apalutamide, enzalutamide, and darolutamide. And those are definitely three options I would consider in this patient. And then beyond that, we also deal with the drug interactions in the clinic. We also deal with copay issues. We also deal with other issues. Many other issues, like how many times you have to take the pill and so on. But in this case, I think drug interaction and copay will be the major players in my mind. Major issues in my mind.

Zachary Klaassen: Absolutely. So you mentioned ARANOTE. And this was presented at ESMO 2024. And so we have it in the NCCN guidelines, still pending FDA approval. In your mind, what's the appropriate patient where this would maybe be favored versus the other combinations we've talked about?

Neeraj Agarwal: I know we are talking about recent advances today. And definitely, you brought up ARANOTE trial in our discussion. So darolutamide is a very good option in addition to other ARPIs for our patients. So when I look at my patient in my clinic with a newly diagnosed mHSPC, I'm really trying to decide between triplet and doublet.

And then within the doublets, I'm looking at whether it is abiraterone, which is androgen synthesis blocker versus potent AR blocker. And then we dive into other aspects. Copay and other issues like drug interactions, for example. So I noticed that patient is on apixaban. So definitely, if I recall correctly, I obviously rely a lot on my pharmacy support.

But my pharmacist has told me in the past that many of these anticoagulants do better with darolutamide. So in this context, and I know why you brought up darolutamide, because the patient is on anticoagulant, which may interact with enzalutamide and apalutamide. So from that perspective, darolutamide is a better fit in this patient. But at the same time, if there are copay issues which can come up, I would change the anticoagulant in this patient to a more compatible anticoagulant, if I'm using enzalutamide and apalutamide.

Zachary Klaassen: Yeah. That's well said. I think you brought up a great point. The pharmacists really are key in these discussions and making sure that-- they're basically double checking everything that we're trying to decide on the front end in a busy clinic. So I think that's a great take home message as well.

One thing that's interesting. And I practice in the South. I have a lot of African-American patients. I know you guys have published extensively some real world data looking at some of the differences and outcomes with race. Obviously retrospective data. But does this play into your decision making? If it does, how does it play into it?

Neeraj Agarwal: We know now that even though being Black has historically meant inferior prognosis, Black patients do equally well, if not better than white patients, as far as clinical trials are concerned with all these ADT plus ARPI trials. Not one, but there are numerous studies now showing the same thing.

Zachary Klaassen: Yeah.

Neeraj Agarwal: I think the historically, poor prognosis of Black patients was probably associated with access to care and not the biology of disease. In fact, they may have more androgen-sensitive disease, and they may respond better to androgen deprivation therapy, along with deeper androgen blockade with an ARPI. So that's my take on the race part, that being Black doesn't mean inferior prognosis, if they get equally good care by us.

Zachary Klaassen: Yeah. My final question is, what are the most important aspects of treatment that you discuss with patients and family as part of that shared decision-making process? We've hit on this a little bit, but maybe just pull it all together for our listeners.

Neeraj Agarwal: Again, family plays a big role. Caregivers play a big role in allowing our patients to make a decision with our help. So this is a shared decision-making. Patients have to make decisions with our help. And most important factors which play in their mind is definitely beyond the efficacy parameters. Yes, delaying disease progression is important, living longer is important.

But side effect profile. Will I be able to do my job? Will I be able to stay away from your clinic, Doc? That's one of the most important point brought up by my patient. How often I will have to come to your clinic. How often I'll have to do the lab test. How often I will be spending time in the infusion room. How much time I'll be spending dealing with the side effects. And from that perspective, definitely there are some drugs which are superior to other drugs.

Second is the copay issue. The financial aspect is something which definitely plays a big role in my patient's mind. So the copay issue, copay assistance, and definitely recent change in policies, which will allow our patients to use the copay assistance provided by different foundations or pharmaceutical companies to be able to use towards their copay is definitely going to be very helpful.

So the copay accumulator program, which used to be in place, and then maximum-- like a cap on the copay. If there is a cap, patient knows how much they are going to spend on a given drug. So I think all those factors-- side effect management, efficacy, copay issues, visits to the clinic, all of them play a big role. And ultimately, our patients are very smart. Most of them are very smart. They have great family support in most of the cases.

And if not, we can arrange social work support for them. We can be their allies, if they don't have families. We do see those patients who come alone in their clinics. But definitely, shared decision-making is ultimately the most important part of our patients' treatment.

Zachary Klaassen: That's well said. Neeraj, Always a high-level discussion and fun chatting with you. Maybe a final take home message for our listeners on this case.

Neeraj Agarwal: We have multiple life-prolonging therapies available for our patients with metastatic hormone sensitive prostate cancer. We have docetaxel approved for last 10 years now. We have ARPIs approved for five years now. And we have these drugs, which significantly improve life expectancy not statistically, but in a clinically meaningful fashion. So it is unacceptable now to not offer these life-prolonging therapies to our patients. It is unfortunate to see many of our patients in the community, across the country are still being treated with ADT monotherapy, and let's try our best to stop that from happening.

Zachary Klaassen: That's a great way to wrap it up, Neeraj. Thank you, as always, for joining us on UroToday.

Neeraj Agarwal: Thank you, Zach, for having me.