Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist, and I'm pleased as always to be joined by Dr. Oliver Sartor, medical oncologist. Today we're going to be discussing metastatic hormone-sensitive prostate cancer and treatment intensification, particularly focusing on treatment selection for triplet therapy. Oliver, thanks so much for joining us on UroToday.

Oliver Sartor: Great, delighted to be here. And thanks for having me as always, Zach.

Zachary Klaassen: No, absolutely. So I think just to set the stage for our listeners, Oliver, maybe just very high level discuss where we've come in the last decade for treatment intensification for metastatic hormone-sensitive prostate cancer.

Oliver Sartor: Sure, ADT has been the standard in one form or another since 1941. Hugely important. ADT estrogen data that was published way back when, Nobel Prize-winning work 1966. That remained the standard of care until there was the introduction of some of the older oral anti-androgens, things like flutamide and nilutamide, bicalutamide, but they really didn't change very much.

What really initiated the change, first reported in 2015 by Chris Sweeney, was a trial called the CHAARTED trial, which showed ADT docetaxel was actually superior to ADT alone, particularly for those who had high-volume metastatic disease by definition. That set off a cascade of studies that were initially altered in part by the ARPI, the androgen receptor pathway inhibitors, from studies that came in from STAMPEDE and others.

The addition of abiraterone to ADT and then subsequently the androgen receptor antagonists, things like enzalutamide, things like apalutamide, things like darolutamide all came into play showing superiority of intensification. If you go to the next step, there were two trials, both of which were attempting to build upon the ADT docetaxel backbone.

Yeah, so the backbone of ADT has been present as stated ever since 1941. But if we move forward, we have the addition of docetaxel in the CHAARTED trial, originally presented by Chris Sweeney in 2015, unequivocally demonstrating that docetaxel added to ADT and intensification could actually lead to a better outcome.

That established an intensification regimen that improved upon ADT, but quickly following were a series of studies using the ARPI. First of all, with abiraterone and the STAMPEDE trial, and then moving on to corroboration with other trials using the abiraterone and then enzalutamide and then apalutamide and then darolutamide. Now, as it turned out, trying to build upon the ADT backbone was quite important when using docetaxel.

So two trials started to build upon that ADT docetaxel backbone. One of these was the PEACE-1 trial, which took abiraterone and added it to ADT docetaxel. And then a second trial called the ARASENS trial, which took ADT docetaxel and added in darolutamide. And in each case, the ARPI added value over the ADT plus docetaxel alone. So now we've intensified both with the ARPIs and intensified with docetaxel on top of ADT.

And now we've brought in the triple therapy that is yet to be proven in terms of adding value of docetaxel plus an ADT ARPI. There's never been a study to show that docetaxel adds to ADT and an ARPI. And this is one of the big major questions today that we have to evaluate. But I'll simply say that the triple therapy has been adopted as an aggressive approach, particularly for those with high-volume disease, particularly for those who are younger and able to tolerate the side effects of chemotherapy.

So when we think about intensification today, I think everyone should be able to get an ADT and an ARPI. And selected patients may be treated with a triple therapy, which would include ADT, docetaxel and an ARPI, with either abiraterone or darolutamide being the, in my opinion, ARPIs of choice given the well-controlled trials. So that's a little bit of the history going all the way back to Dr. Huggins in 1941 up to the present day of the ARASENS trial.

And most recently, by the way, with another trial with darolutamide called the ARANOTE trial, which was simply ADT and darolutamide, showing superiority to the ADT alone.

Zachary Klaassen: Yeah, no, that's perfect. And I think you make a great point, and I've heard this several times, about we don't know what the addition of docetaxel is to an ARPI plus ADT. So in that context, Oliver, how do you select patients for triple therapy? Who's the patient walking through the door where you say this patient's the best candidate for triple therapy?

Oliver Sartor: Great question. So first of all, I'll give you a specific example and then we'll be more generalized. The last patient that I started triple therapy on was about a 58-year-old guy who came in with high-volume metastatic disease. He had multifocal bone disease. He had disease that had spread throughout his skeleton, probably with 25 different metastases. He did not have liver metastases, but he also had some lymph node metastases.

And he was relatively young, relatively healthy, did not have PSA as a measurement prior to the diagnosis, came in with symptoms. And I thought he would be chemotherapy tolerant. And I think that he would benefit from triple therapy. And I used ADT in combination with darolutamide built on the ARASENS trial with docetaxel times six cycles, 75 mg/m2, Q3 weeks. You don't need to give more than six. The data from CHAARTED and forward was with six cycles of docetaxel.

But the bottom line is that the patient has done very well. We measure in part the nadir PSA that we achieve as being a near-term efficacy marker. And he did achieve a PSA of less than 0.2, which would put him into a more favorable prognostic category.

Zachary Klaassen: No, you're absolutely—I think you're right. Across the country, we see certainly a lot of these younger patients, high PSA, high disease burden. I think that's the patient where at least the conversation is appropriate for triple therapy. When I look at the data from ARASENS, it's great data. It's a chemo plus ADT control arm. Obviously overall survival was positive, making it a positive trial. Are there other secondary endpoints that you use to talk to patients, maybe time to CRPC, pain progression, time to next neoplastic therapy? Is there other endpoints you use just to give them an overview of what potential benefit they may have?

Oliver Sartor: Yes, and time to CRPC is really important. The longer patients don't have CRPC, we feel like we're controlling the disease quite effectively, and that is unequivocally prolonged. I also talk about the quality of life. And unfortunately, with the docetaxel, there's a deficit in the quality of life that can persist beyond the actual six cycles.

So I'll make sure that people understand that I'm a little wary of people who might have baseline neuropathies, which could be a docetaxel-induced side effect. I talk to them about the risk of neutropenia and febrile neutropenia in particular, which may be as high as 12% with a triple regimen including docetaxel.

But the benefits are going to be in the disease control, and the deficits are going to be in the quality of life and potential febrile neutropenias, and rarely the issue of neuropathies can arise. So I try to give a balanced view, but the choices are based on, to me, not only the volume of disease, but the ability of the patient to tolerate the therapy without difficulty.

I'll take another example of a patient I did not use triple therapy. He was about 82. He came in and had a little bit of neuropathy from a baseline diabetes. And I did not choose to offer him triple therapy because I thought that the quality of life and neuropathy in his age would be mitigating factors.

So to me, it's a little bit of a judgment, a little bit of an art form. And as it turns out, I think I'm probably in the majority there. Triple therapy is not for everybody, but for the young, aggressive patient, it's something that we should consider.

Zachary Klaassen: Yeah, that's well said, Oliver. A great discussion as always. Any take-home messages, final concluding remarks we haven't touched on yet?

Oliver Sartor: Well, we are in a very timely way, I think we have a bit of a discussion about our former president. President Biden has been diagnosed with metastatic disease. We don't know much about his particular scenario other than he came in with urinary symptoms, found to have a prostate nodule. I suspect that PSA screening had not been done, but we don't know that—there's been no divulgence of the PSA.

And given his age, I think that he would be an excellent candidate for an ADT and ARPI. It'd be a pretty careful discussion on somebody in his age group as to whether or not you wanted to include a triple therapy. So that's just your timely update of the news this week.

Zachary Klaassen: Yeah, absolutely. Our patients out there all have multiple options. It's a great opportunity for shared decision-making. And as always, Oliver, we thank you for your time and taking time out of your busy day to join us on UroToday.

Oliver Sartor: Thanks for having me.

Zachary Klaassen: Thank you, Oliver.