Balancing Treatment Intensification, QOL in mHSPC: Insights on Patient Management, Bone Health

A roundtable discussion, moderated by Pedro Barata, MD, of University Hospitals, highlighted the evolving treatment landscape of advanced prostate cancer, including hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC). The panelists analyze expanding treatment intensity, the utilization of androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs), and integrating patient-reported outcomes (PROs) in care. Dr. Barata was joined by Andrew Armstrong, MD, MSc, of Duke University School of Medicine; Cora Sternberg, MD, of Weill Cornell Medicine; and Evan Yu, MD, of UW Medicine.

In the fourth part of our series, the panelists discuss PROs and potential patient comorbidities, along with the types of treatments that can be offered in regard to maintaining quality of life.

View the next segment of this roundtable series: PEACE III: Implications for Radium-223 and Treatment Sequencing in CRPC

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Dr. Barata:
Cora, let me ask you – back to the point around quality of life and patient-reported outcomes. The regulatory agencies have worked with investigators and institutions to give a strong recommendation to gather information on how our patients are feeling while they go on these treatments.

Since we’ve prolonged time and they live longer, it’s very important to make sure they’re not being harmed by giving them more therapies. So, it’s always a hard topic. I feel like we don’t talk as much about patient-reported outcomes in quality of life in general. We look at the curves at times, but it’s sometimes hard to interpret. How do you take that?

Dr. Sternberg:
First of all, I agree with everything that was said, but we must also take into account the comorbidities and the age of our patients. So if our patients – even if they have visceral disease – if they’re 89, 90 years old or have serious heart problems or something, these are not the patients we’re going to start on triplet therapy.

We really need to take into account the patient that we’re talking about and their quality of life before and after. Adding chemotherapy and triplet therapy is more serious than just doing doublet therapy. So I think that that’s really important. And then the other thing is that, when patients are on the triplet therapy – for instance, in the ARASENS trial – they’re on it for longer because they do better. So they have more time to develop more side effects.

This often happens in many trials when patients are on treatment for a longer time or they’re on twice as much; they have twice as much time to develop the side effects. I don’t think that we have one quality of life instrument that’s really dedicated to all of this. There are geriatric scales and EORTC quality of life scales that look a lot at urinary symptoms and other kinds of things, but I don’t think that we have universally decided that this FACT-P or this EORTC is the one that we should be using for elderly patients, or for patients who are receiving this kind of treatment. And I think we need that.

Dr. Barata:
Absolutely. And so if I were to summarize, for our audience, even though we’re giving more therapies to patients, quality of life is shown in all the trials, to be at least preserved, if not better. In other words, more is not worse in this case. So I think that’s one message. And the second one, which I think is implied implicitly, what you are describing is, we all assume treatment intensification should be done for the vast majority of the patients, assuming that life expectancy is driven by prostate cancer.

So if we see a patient where life expectancy is shortened because they have comorbidities due to advanced age, the patient is very frail. So every time we answer the question “do we think this patient will unfortunately die from prostate cancer?” we should definitely consider the treatment intensification. In my practice, where life expectancy is really short, including the times that I spend at the hospital in service, it’s about 10, 15%.

So I would argue that of eight of ten patients that I know with metastatic prostate cancer, they should be offered a treatment intensification; not only for the benefit in regards to the addition of ARPI with or without chemo, but also because we are actually not harming them. Patients are telling us that they feel the same if not better. Do you agree with this?

Dr. Sternberg:
Treatment intensification with a doublet, yes. Once we start talking about a triplet, I think that that’s something different – and I participated in the ARESENS trial, I believe in the data. But whenever we have a clinical trial, we always select the patients that are on it, and that’s not the same exactly as real-world data. When you see the real-world data afterwards, it’s often very different. So I think patients are highly selected to go on trials. So I agree with you that most of the patients can be on doublet therapy, irrespective of their age. That is what I try to do and not just give ADT. But for triplet therapy, I think age is very important and I tend to give it more to younger patients who are fit for chemotherapy.

Dr. Barata:
So since you mentioned that, that is interesting – because the real-world data suggests that we are probably not using chemotherapy more than 10% of the time. Do you have a different experience in academia?

Dr. Armstrong:
Certainly, in this ivory tower here, we’re probably more like 50, 60%. But I think that communication around quality of life involves patient trade-offs. There’s going to be a drop in quality of life if you pick triplet therapy for about three to six months, and then a rebound. And then the goal is to delay that deterioration in quality of life due to the disease and the comorbidity of disease progression, which really leads to the massive quality of life drop when you get to metastatic CRPC. And so the goal is to delay that into the future. And so you’re having that conversation with patients right up front. A little bit of a drop in the quality of life early, to prevent a bigger drop and delay that regarding triplet therapy.

With doublet therapy, I think you do have more side effects. Even some of the best ARPIs that we have, there’s always a little bit more. Certainly there’s more costs, so there’s financial toxicity for some patients. But you see a bit more fatigue and hot flashes and effects on skeletal health, stamina. That’s why we were talking about intermittent therapy initially. This is now lifelong continuous therapy, and so we can’t neglect that. It has some effects, but the goal is to minimize that by maximizing survivorship like we talked about monitoring, encouraging fitness goals and a healthy diet and things like that. Bone health as well. We do see increased fractures and frailty in our patients. So having those conversations up front would probably help improve those numbers in the community.

Dr. Sternberg:
We should be looking at bone density in all of our patients. We should talk about their diet, we should talk about exercise. These are so important.

Dr. Barata:
As they live longer, the topic of cardio-oncology comes up often. Absolutely. Since we’re on this topic, how do you address patients with bone metastasis and bone modifying agents? I find it sometimes is a topic of confusion. One to prevent osteoporosis, osteopenia and the other one to prevent scalp-related events. Evan, can you just go through how you handle bone-modifying agents for patients with metastatic hormone-sensitive disease?

Dr. Yu:
Yeah, absolutely. I discuss the risk of developing osteoporosis with patients. I have them all take calcium, vitamin D. I talk to them about exercise and some resistance exercise training. Those are the simple things that I do. And then I do a baseline DEXA scan and I do DEXA scans for surveillance.

I used to do it more frequently, but I now probably do it about once every other year. So if you do it more frequently than that, you don’t really see enough change to act on it. But about once every other year. And I do also use agents like zoledronic acid and denosumab. I use the 60 milligrams every six month dose there for osteoporosis. Now, just to be clear, zoledronic acid has been looked at as a potential anti-neoplastic or survival drug. In the STAMPEDE study, it looked at an older CALGB study that accrued about 90% of the patients and never finished. But there was no survival signal there. So for that reason, I don’t use the doses and the frequency that we use for zoledronic acid, and we used denosumab for skeletal-related events, which would be for metastatic castration-resistant prostate cancer. I use it just for the osteoporosis.

Dr. Barata:
Whereas for mCRPC, just to remind the audience, you’re not doing it twice a year or once a year with denosumab or zoledronic acid? You do it once a month, once every three months?

Dr. Yu:
The studies would show that you should do it about once a month. That being said, and done with bisphosphonates, we know they hang out for a long time and there have been other studies that have pooled together data on prostate cancer, breast cancer, and other solid tumor patients that show quarterly is just fine.

So I think it also depends, if you look at that population, the goal is to prevent skeletal-related events there. And most of our agents that are fairly efficacious also have an anti-tumor effect, they have some anti-skeletal-related events effect. Now, we may want to talk a little bit later about a study that we recently showed some benefits, here just at ESMO with radium-223, the P3 study where it was critically important to add the bone protective agents.