Making Treatment Decisions in Advanced Prostate Cancer

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In “Beyond Diagnosis: Metastatic Castration-Sensitive Prostate Cancer,” Cleveland Clinic oncologist Christopher Wee, MD, and host John Mangels discuss how clinicians can guide patients through the initial complexities of a metastatic diagnosis.

Each installment of this series explores the key moments in patient care, including building trust, navigating evolving therapies, aligning treatment goals, and supporting shared decision-making.

In this second episode, Wee discusses treatment intensification, choosing between doublet and triplet therapy, selecting androgen receptor-pathway inhibitors, and incorporating patient preferences and genomic testing into treatment decisions.

The following is a transcript of their remarks:

Mangels: Welcome to “Beyond Diagnosis,” where we talk with doctors about treatment decisions and communicating with patients. I’m your host, John Mangels.

Treatment of metastatic castration-sensitive prostate cancer has changed significantly in the last decade. Those changes are creating new opportunities and new complexities for both physicians and patients. How do clinicians choose among expanded treatment options? How do they navigate decisions involving efficacy and risk, quality of life, and patient preferences?

We’ll explore those issues and more with our guest, Dr. Christopher Wee. Dr. Wee is a physician in Cleveland Clinic’s genitourinary medical oncology program. A large part of his practice involves patients with prostate cancer. Dr. Wee, thanks so much for joining us today.

Wee: Thank you for having me.

Mangels: As research findings have evolved, physicians are increasingly treating metastatic disease earlier and more aggressively. When deciding how to manage a patient with metastatic castration-sensitive disease, is your focus on lowering testosterone levels and prolonging hormone sensitivity, treating the effects of metastases, or a little of both?

Wee: All of the above. When we talk about metastatic castration-sensitive prostate cancer, the goal is to help people maintain the quality of life and extend overall survival. A lot of the treatment strategies are aimed at doing all of the above, right?

So androgen deprivation is the backbone for decades. Now, over the past decade or so, we’ve found that we should intensify therapy with a second agent, generally an androgen receptor pathway inhibitor, whether it’s apalutamide [Erleada], abiraterone [Zytiga], enzalutamide [Xtandi], etc.

There are some patients in whom chemotherapy may be appropriate based on the CHAARTED study where they showed that in patients with high-volume disease, chemotherapy can improve outcomes compared to androgen deprivation therapy [ADT] alone. So generally speaking, it’s going to be one of those strategies, ADT plus one of these oral agents, plus/minus chemotherapy.

Mangels: We talked earlier about the value of PSMA [prostate-specific membrane antigen]-PET in determining disease burden. I’m wondering about the risk of further progression. How are you evaluating that and how does that factor in your treatment choices?

Wee: Right, so that’s a great question. There are two ways disease can progress from castration-sensitive prostate cancer. It could just be a PSA only progression, at which point the number could be going up, but we don’t necessarily see any new spots in imaging. In those cases, it becomes a question of whether or not you even necessarily need to change treatment at that point if just the number’s going up, but you could.

If there are new spots of disease emerging or measurable disease — so soft tissues, lymph nodes enlarging — then I think you have more urgency to try to consider a treatment change for metastatic castration-resistant prostate cancer. So imaging should be considered when there’s a rising PSA, unexplained symptoms.

If a PSA is controlled and a patient’s doing well, the optimal duration of imaging just serially is unclear, though I usually consider conventional imaging maybe every year or so.

Mangels: And again, we’ll talk more about your follow-up strategy a little later, but let’s get into treatment choices at this point. So research has largely answered the question of whether treatment intensification with combination therapy actually works, but many patients with hormone-sensitive disease are still only being treated with ADT. Why is undertreatment still an issue?

Wee: I don’t think we necessarily know the reason why. When we look at the national trends, there have been multiple reports showing that a significant number of people are not being treated up to the standard of care, which is unfortunate given that many of these agents improve not only progression-free survival, but overall survival.

And so it probably is multiple factors, but our goal here at Cleveland Clinic and other specialty medical centers is to help people make those informed choices so that we can make sure that we are treating up to the standard of care.

Mangels: I wonder if in the back of some physicians’ minds is, “I want to hold something in the arsenal for when the transition to castration-resistant disease occurs and still have something left to give.”

Wee: Yeah, that’s generally not my philosophy because I don’t like to “save a treatment” if I want to give the best treatment for the patient that’s sitting right in front of me.

We do also know that a lot of people don’t see subsequent lines of therapy. You may never get to a point where a patient’s in good enough shape to be able to take another line of therapy. So I don’t like holding things. I like using them… what’s the best combination at that time.

Mangels: There’s still a lot of discussion about doublet versus triplet therapy. How do you approach that decision?

Wee: So let’s take a step back. We know that ADT plus some of these pills like apalutamide, abiraterone, enzalutamide, improve overall survival compared to ADT alone in randomized controlled trials. These trials take years to read out because patients fortunately can do well for so many years.

In the interim, they had a trial called ARASENS where they randomized patients to ADT plus darolutamide [Nubeqa] plus docetaxel versus ADT plus docetaxel chemotherapy. And the patients with the triplet did better than ADT plus docetaxel.

What we do not know is whether three, that is ADT plus pill plus chemo, does better than ADT plus pill. There have not been randomized trials. There are ongoing cooperative group trials to try to answer this. We don’t have the answer yet.

So how do I approach this? Let’s say if someone has low-volume disease, I probably won’t be adding on chemotherapy given the fact that when we had data back in CHAARTED, chemotherapy didn’t really help patients with low-volume disease.

If a patient has high-volume disease, I’ll discuss whether or not chemotherapy may make sense in that situation. If a patient is absolutely adamantly doesn’t want to get chemotherapy or they’re not in a good place health-wise to get chemotherapy, completely reasonable to do a doublet. But if someone wants to be aggressive and is in good health, then I think that’s the time to consider a triplet.

Mangels: Let’s talk about androgen receptor pathway inhibitors. So as you said before, comparatively, there haven’t been head-to-head trials of those modalities. So how do you make the decision between one versus another versus another?

Wee: Yeah, I’ve used all of them at some point or another. I think the first thing, if we’re going to use a doublet situation, there are three that have proven overall survival benefit compared to ADT alone, that being apalutamide, abiraterone, enzalutamide. Darolutamide has a progression-free survival benefit, but no overall survival benefit.

Now, that could be because the trial was done later outside the U.S., but I can’t necessarily say it’ll help people live longer. So I tend to, if I’m using a doublet, use one of those three previously mentioned. And that’s reflected in the NCCN [National Comprehensive Cancer Network] guidelines as those are the Category 1 recommendations.

Beyond that though, it really comes down to contraindications, physician preference. It’s not wrong to use one over the other in that situation. I think it’s good as long as we’re giving something before we get too in the weeds and too prescriptive about which specific one someone should or should not use.

I think it’s the fact that if you have anything on board is better than just doing ADT alone in most of these cases.

Mangels: How much, if at all, do you involve your patients in the kinds of choices that we’re talking right here between [androgen receptor pathway inhibitors], for example, doublet versus triplet therapy? Do they factor into decision making?

Wee: Well, the doublet versus triplet, certainly, because I’ll say, look, I think this could be a situation where chemotherapy could be beneficial. We don’t have the head-to-head data saying definitively, and then it comes down to the patient’s preferences, how hard is the chemotherapy going to be, how long are they going to be on chemotherapy.

When it comes to doublet, if a patient says, “My brother was on X drug and I want to do that,” and it’s reasonable, all for it. If a patient is asking for one and it has similar efficacy and no clear benefit of something else, I’m happy to try to accommodate the patient in that situation as long as there’s no contraindications.

Mangels: Let’s talk a little bit further about individualized patient care. Do you recommend your patients that they undergo germline genetic testing or immunohistochemistry or somatic testing?

Wee: So anyone with metastatic cancer I think should be considered for germline genetic testing. Obviously there are some individuals who will have even higher pretest probability, we’ll find something such as if they have multiple relatives with other cancers or a very young age at diagnosis. That’s not necessarily to help them directly, but could help their family.

And then we discuss the risks and benefits of germline testing, and then if they find something that may be of significance, we get them to see the genetic counselor or they could go to the genetic counselor themselves directly first.

We also recommend somatic testing. And previously this had not really made a difference in the hormone-sensitive setting up until the past recent months, for example.

The main thing we’re looking for here are HRR mutations — homologous recombination repair — BRCA being the most common one that we familiarize ourselves with, because in the second-line setting… so first-line, castration-resistant, PARP inhibitors have shown benefit in those situations.

More recently, however, we do have an approval of niraparib plus abiraterone combination [Akeega] in the hormone-sensitive setting if you have a BRCA mutation. And even more recently for people who are PTEN deficient by immunohistochemistry staining, they can get capivasertib [Truqap] plus abiraterone.

Mangels: Literally a month ago that was approved, right?

Wee: Exactly. So I think the importance of testing, we’ve been trying to push for it because [the] last thing you want is to have progressive disease, then need to wait on the result. But now it really makes the urgency of testing even more paramount to make sure you understand all your options.

Mangels: Thanks so much for your insights, Dr. Wee. And thank you for joining us on Beyond Diagnosis, where we explore not just what physicians know, but how to effectively and compassionately share that knowledge with patients. See you next time.