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Elena Castro: Hi, my name is Elena Castro. I'm a medical oncologist from Madrid. I'm very pleased to be here today with my colleague, Dr. Alicia Morgans, also a medical oncologist from Dana-Farber. We are here to discuss the State of the Art of Prostate Cancer in 2024, and in this episode, we will focus on the interdisciplinary management of the disease. Hello, Alicia.

Alicia Morgans: Hello. Thank you so much for inviting me to the series. Let's get started on the case. This is going to be a case of a patient with metastatic hormone-sensitive prostate cancer. Mr. JM is a 66-year-old man who presented to his primary care doctor for evaluation of worsening back pain over the preceding six months. He had a history of high blood pressure and high cholesterol as well as reflux disease and was being managed on standard medications for those with good control. He's married and has great family support, three children who live nearby, and he's a retired banking executive.

His primary care doctor performed X-rays of the spine that were concerning for metastatic cancer. His primary care doctor ordered, among other things, a PSA to try to understand whether this might be contributing to what they saw on the X-ray. The PSA was elevated at 47, and so he was sent to the urologist for an evaluation, and the urologist performed an MRI-guided prostate biopsy. The biopsy demonstrated that he had grade group 4 disease, so pretty advanced and aggressive high-grade disease in eight of 12 cores bilaterally. He underwent a staging workup for this, and it demonstrated multifocal bone metastases and de novo high volume metastatic hormone-sensitive prostate cancer because of those bone metastases and also because he had a liver metastasis and pelvic lymph node involvement.

He talked about his options for treatment and thought about options including ADT and an androgen receptor signaling inhibitor versus ADT and an androgen receptor signaling inhibitor plus docetaxel or a triplet approach. We, of course, know that the triplet approaches include either chemo hormonal therapy with darolutamide or chemo hormonal therapy with abiraterone based on the ARASENS and PEACE-1 studies, respectively. Ultimately in that conversation, this patient reviewed that he had a liver metastasis, was relatively young age, was quite fit, had great family support, and really wanted to be as aggressive as he could against the cancer in this setting using that sort of multi-pronged approach of a triplet regimen.

He was ultimately treated with ADT, docetaxel, and darolutamide, and he did very well in terms of tolerating it. I would say he chose darolutamide rather than abiraterone because he also wanted to have some steroid-sparing approach, especially since the darolutamide, of course, continues on with the ADT until disease progression so we wanted to try to limit steroid exposure. His PSA hit a nadir of 0.43.

Elena Castro: Alicia, I think this is a perfect case for triplet therapy. But I wonder whether in your multidisciplinary discussion there may have been other colleagues suggesting that perhaps the patient could have been also treated just with an androgen receptor signaling inhibitor alone and then after progression treating him with docetaxel since we don't really have data comparing the intensified therapy or the sequence therapy.

Alicia Morgans: Absolutely, and I would say that the urologist who initially saw him for diagnosis in the community really talked a lot about the ADT and the ARSI backbone and really didn't mention the chemotherapy piece. I believe that is because the urologist, exactly as you said, was thinking about the fact that we don't have comparative data of an ARSI plus ADT versus an ARSI, ADT, and docetaxel. We just don't have that kind of a study.

I think when we spoke in our multidisciplinary group here, many of my colleagues really emphasized that they thought this relatively young and fitter patient should get the triplet therapy because we don't know how much it may add, and at some point in time the patient will get docetaxel. It seemed better in this case to try to do it when the patient was younger and fitter than he inevitably would be after time passes in a few years.

I think the other issue here is that when patients have liver metastases, and this was a grade group 4 disease, this was an aggressive prostate cancer, and using a triplet approach allows us to have really multiple approaches to try to get to the heterogeneity of the cancer cells. Certainly, when we think about liver metastases, we're often thinking that these may be cells that might be best approached with chemotherapy really to get a robust and rapid response in the liver as well as in other places. Yes, there was absolutely conversation, and if the patient really favored doing the doublet approach, this would've been his choice, and we would've been very happy to support him in that as well. But I think in this case, this was both the ultimate recommendation of the multidisciplinary team as well as the preference of the patient.

Elena Castro: I probably would have done the same. It was a very aggressive presentation. How did the patient respond to this? How long did the response last?

Alicia Morgans: Yeah, so the response lasted for about a year and a half, and I would say we used our multidisciplinary team to support the patient through the treatment and really our nursing staff helped the patient with any side effects, particularly those related to the chemotherapy. He tolerated it well because I think in general people do tend to tolerate docetaxel pretty well, so using all of the support around our team to get him through that and then ongoing support as he continued, as I said, for about a year and a half.

But around 19 months, he did start to have a PSA that was gradually increasing. Went up to 2.7 and then really started to move, up to 10.53. He started having some more symptoms at that time. He had fatigue, and he had an increase in his back pain. Certainly, we were concerned that this could be related to disease progression.

He underwent some scans. Certainly, we focus generally, at least at this point in time, on standard imaging or conventional imaging first to really document the progression to compare back to his baseline scans or actually the most recent scans because we had been scanning him throughout. He had a bone scan that showed multiple areas of vertebral body, pelvic, and rib involvement really consistent with progression of his disease. His CT scan also demonstrated improvement of the lymph node disease and stability of the liver but some concern for progression of some of the bone lesions and some new bone lesions as well. PSA at that time was up to 33.76. He had already had germline testing. This was negative for actionable alterations. He had not had somatic testing previously, but we were sure to get that at this time of disease progression, and this was also negative for actionable alterations.

In our discussions with the patient, we knew that he was eligible for cabazitaxel and lutetium PSMA-617. To think through those options, we had to see if he was truly going to be eligible for lutetium by getting a PSMA PET scan, which of course is the way that we identify whether his cancer has that biomarker of PSMA. He did have a PET scan. This was really consistent with his disease expressing PSMA and really showed that all of those areas were expressing. He had the decision to make between cabazitaxel and lutetium.

At the end of a shared decision-making process, he decided that he wanted to pursue treatment with lutetium PSMA-617. He did get his six cycles, one every six weeks, and tolerated it well, though he did have some cytopenias during that treatment, mild dry mouth, but he did have disease stabilization. He did not end up having progression during treatment, which can be a concern, especially with patients with liver metastases. The multidisciplinary team was able to support him, including nuclear medicine at this time, to support him through his treatment.

Elena Castro: I think it makes a very nice case, and we are going to be confronted with these situations more and more. I think in my case, we would have had a very long discussion about cabazitaxel or lutetium because it is true that the only study that has compared these two treatments is the TheraP study, which is a Phase II. For overall survival data, we don't really have very, very strong data to support our decisions.

But it seems that these patients treated with lutetium, as you presented, have more PSA response, and they tolerate it better than cabazitaxel, although it seems that there's no significant difference in overall survival. I think for these patients, we will need to have long discussions and take into consideration their preferences, of course. It is good to have options, isn't it, and be able to offer different possibilities?

Alicia Morgans: I could not agree more. It's really, really good for us to have options, and it's actually, I think, fantastic that we have options that we know can both prolong survival, and it looks to be relatively similar between the two. When we had that shared decision-making conversation, we really discussed that he would be getting both of these treatments pending performance status, and ultimately we just needed to figure out which one went first and which one would go second. It was through that conversation and some of his preferences around having less frequent treatments, so once every six weeks versus every three weeks, and maybe having a little bit more flexibility in his timeline and schedule, that was a main driver for him to choose lutetium PSMA-617.

I think the other issue is that he did look at the TheraP study and some of the patient-reported outcomes, as you said, suggested that patients may have tolerated that a little bit better. I think a PSA response rate being better is not necessarily something that will drive me to push for that option, but when patients feel better or report that they're feeling a little bit better, that certainly impacts the patient's decision-making. Because survival is really similar, I think it's nice that we can say, "You'll do one now, we'll do one next, and we'll get everything that we can into you to try to control this cancer."

Elena Castro: Also, in this study, there is a small fraction of patients, some patients received lutetium after cabazitaxel and also cabazitaxel after lutetium, and there doesn't seem to be too many issues with tolerance and side effects in those patients. As you were mentioning earlier, there may be the possibility of sequencing different agents for our patients.

Alicia Morgans: Absolutely.

Elena Castro: Yeah. Thank you very much, Alicia, for joining me, and thank you all for watching. Don't miss the next episode of this series on the State of the Art of Prostate Cancer in 2024.

Alicia Morgans: Thank you.