expert roundtables

The Shift Toward Earlier Use of Life-Extending Therapies and Combinations in Advanced Prostate Cancer

by Glen Gejerman, MD, Daniel J. George, MD, William K. Oh, MD, and Oliver Sartor, MD MD, FACS

Overview

Recent advancements in the treatment of prostate cancer include the approval of 5 new life-prolonging agents. These advances have the potential to change the treatment paradigm. Leading experts discuss the optimal timing and use of these new therapies.

Q:

How do you identify who should receive more aggressive therapy earlier and how to sequence or combine these therapies to potentially enhance outcomes?

Expert Commentary

Daniel J. George, MD

Professor of Medicine and Surgery
Divisions of Medical Oncology and Urology
Director, Genitourinary Oncology
Duke Cancer Institute
Duke University Medical Center
Durham, NC

I look at this field as having made tremendous progress in the last 7 years, with the addition of 5 new life-prolonging therapies. When I look at a patient who is otherwise healthy enough to live 3 or more years, regardless of age, then – to me – that’s someone who is ultimately going to die most likely from his castrate-resistant disease. That’s the kind of patient I’m trying to figure out how best to treat with all of those modalities. Except for the overlap between abiraterone and enzalutamide, these are really different mechanisms and potentially additive mechanisms, so I think that’s one of the things we will need to find out through some larger cohort studies, registries, or sequencing studies. Until we have that data, my goal is try to keep these patients going with as good a quality of life as possible, by sequencing or potentially adding these therapies together.

“Until we have that data, my goal is try to keep these patients going with as good a quality of life as possible, by sequencing or potentially adding these therapies together.”

Daniel J. George, MD

The idea that all of these therapies are monotherapies, stand-alone, based upon their FDA approval is a little bit of a limited context in which to evaluate their efficacy. There is no doubt that a drug like radium-223 can be given with multiple other agents. Whether or not there is a synergy in doing that or not remains to be seen. However, in terms of just the efficiency of treating patients rather than waiting for disease progressions to happen, it makes a lot of sense to say that this is one of the agents that could be combined with others, in the sequence of things. With that rationale in mind, recognizing that we don’t have level 1 evidence for it yet, we certainly have evidence for its efficacy, and efficacy with other supportive care measures. It makes sense to me in bone-dominant or bone-only metastatic patients to consider this earlier in the treatment course.

Glen Gejerman, MD

Co-Director, Urologic Oncology
Medical Director, TomoTherapy
John Theurer Cancer Center
Hackensack, NJ

I completely agree. As someone who delivers a lot of radium-223, I’m sometimes frustrated that, when a patient is referred to me bed-ridden and heavily pretreated, no one ever really gave a thought to using radium early. We know from the original ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients) trial that only about 58% of patients got all 6 infusions. When I see a patient who is heavily pretreated, I know I am not going to be able to give him all of the medication. If I see someone who is early on in the process – where he has early symptomatic castrate-resistant prostate cancer (CRPC) and some metastases – those are the patients I think we have the greatest impact on. We’ve seen some studies now indicating that asymptomatic patients were more likely to have a better prognosis and a longer disease-free survival, or rather, secondary skeletal event symptoms, as well as overall survival. Then there’s also some interesting laboratory evidence suggesting that radium-223 may impact the cancer cells so that they can be more susceptible to T-cell–mediated lysis. That interaction, although we’re going to need the bigger studies to see how to combine these drugs, supports earlier intervention in symptomatic patients, where it’s appropriate, and is something that we should be shifting toward.

“If I see someone early in the process – where he has early symptomatic CRPC and some metastases – those are the patients I think we have the greatest survival-benefit impact on.”

Glen Gejerman, MD

William K. Oh, MD

Chief Medical Science Officer, Sema4
Clinical Professor of Medicine
Division of Hematology and Medical Oncology
Icahn School of Medicine at Mount Sinai
New York, NY

These different drugs were approved around the same time and have very different mechanisms of action. What we’re seeing already is the shift toward the earlier use of all of these treatments. We have already talked about how in hormone-sensitive prostate cancer metastasis (mHSPC) we’re now using docetaxel chemotherapy. That’s an example of how we’re bringing more systemic therapies earlier into the disease course. There are ongoing clinical trials looking at the use of AR-targeted therapies in M0 patients, patients without metastatic disease, who have CRPC. The question is, for example, when should we be using sipuleucel-T? Obviously, we’ve always talked about this approved immunotherapy being used in asymptomatic patients with mCRPC, but early in the disease course. We just heard Dr Gejerman talk about how radium should probably be used earlier than we typically have been using it, which is often at the very end of life – in which case, it really probably wouldn’t have the same level of benefit. I think that this is the struggle we’re having because we don’t have level 1 evidence about the optimal sequence, and it is likely that the optimal sequence is going to be different from patient to patient. So we have to remember that there are going to be specific scenarios in which certain drugs may be particularly valuable. For example, the androgen receptor (AR) pathway may be very valuable in a large subset of CRPC patients, However, in some patients, they may blow through AR-targeted therapies because the androgen pathway may not be the main driver of their progression. Those patients may need to be switched earlier to chemotherapy, for example, if they had a very short primary response to androgen-deprivation therapy (ADT) or primary androgen deprivation. Certainly, if someone has a very short response to one AR-targeted therapy like abiraterone or enzalutamide, then it doesn’t always make sense to switch to the other, which is something that I know a lot of clinicians do. It’s just something that we’re still figuring out in terms of prognostic markers. I think it’s important to look at the totality of what our choices are for a patient. We have to think about using these drugs earlier, but also try to be as rational as possible about which drug to use, in which sequence, and really to try to benefit patients by not waiting until they’re so symptomatic and so late in their course that they’re not going to benefit from the drug.

“We have to think about using these drugs earlier, but also try to be as rational as possible about which drug to use, in which sequence, and really to try to benefit patients by not waiting until they’re so symptomatic and so late in their course that they’re not going to benefit from the drug.”

William K. Oh, MD

Oliver Sartor, MD

C. E. and Bernadine Laborde Professor of Cancer Research
Medical Director, Tulane Cancer Center
Associate Dean for Oncology
Tulane University School of Medicine
New Orleans, LA

What’s kind of interesting is that, in some ways, I think the field is sort of a victim of its own success. We’ve had so much progress with abiraterone, enzalutamide, cabazitaxel, radium, and sipuleucel-T – all since 2010. When we look at the level 1 evidence we have, there is a lot of it. However, we have very little in the way of comparative studies and very little in the way of sequential concepts that we’ve tested prospectively. It really is a little bit of a conundrum. I think for something like sipuleucel-T, bringing it early on makes very good sense. There’s a good hazard ratio for those with a low PSA as compared to those with a high PSA. Paul Schellhammer published a manuscript based on their large prospective trial, the IMPACT (Identification of Men With a Genetic Predisposition to Prostate Cancer) trial. I think the way that clinicians are thinking today, they’re typically using one of the hormones pretty early, either abiraterone (Abi) or enzalutamide (Enzal).

There are prospective trials comparing Abi +/- radium and Enzal +/- radium, but we don’t have those results yet for radium. We really are not going to be able to benefit those patients very much. We just don’t have adequate amounts of doses to be able to get into those patients before they decline clinically. Then, of course, the chemotherapy that we’ve been using for years, docetaxel, is now kind of falling into the second-line setting for many, many patients. There’s something intriguing that I’ve noticed: sometimes we can treat with chemotherapies and then re-sensitize to the hormones. We might even take a patient who’s resistant to Abi, treat him with docetaxel, and come back to Abi again, and then have a sensitive patient. There’s so much to learn, and it’s really quite intriguing right now with these biomarkers coming out. Dr Oh, I thought you said it very well: which patients are progressing because of AR as being the primary driver, and which of these progressing because of non-AR mechanisms? I think we’re going to figure it out pretty soon and then be able to choose as these therapies all blossom.

“We have very little in the way of comparative studies and very little in the way of sequential concepts that we’ve tested prospectively. It really is a little bit of a conundrum.”

Oliver Sartor, MD

Daniel J. George, MD

Professor of Medicine and Surgery
Divisions of Medical Oncology and Urology
Director, Genitourinary Oncology
Duke Cancer Institute
Duke University Medical Center
Durham, NC

I think those are excellent points, and I think this is where the field is going to have to go. Biomarkers are going to be the most useful for us not so much as prognostic factors but as predictors of who’s going to benefit from which therapies. Because right now, as Dr Oh said, we’re kind of looking at the totality of the clinical data, we’re putting together some customized approaches, and it’s not a “one-size-fits-all” sequence. Or, we are basing it largely on clinical information, which is not really telling us about the biology of the disease. Many of these agents are very biologically targeted in their mechanisms, so there’s going to be resistance based upon certain molecular features of the disease. I think that is going to help us; some of that could be by molecular imaging, some of it could be by circulating DNA or circulating tumor cells, and some of it may be proteomic markers. I don’t really know what is going to be the best modality for measuring that biology in the majority in patients. It may differ from some populations to others, but I think that’s going to be key in really understanding, not just what to start with but also when to switch. Maybe that leads into our next questions: how and when do we measure response or progression in these patients? That is, I think, going to be linked very much to how we sequence or combine therapies in the future.

“Biomarkers are going to be the most useful for us not so much as prognostic factors but as predictors of who’s going to benefit from which therapies.”

Daniel J. George, MD,

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