Advances in Nonmetastatic CRPC


An overview of drug approvals for nonmetastatic castration-resistant prostate cancer (CRPC), and discussion regarding the potential utility of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) to guide treatment decisions.

Alicia K. Morgans, MD, MPH: Let’s talk about our next section, which is management of nonmetastatic castration-resistant prostate cancer [CRPC]. Sandy, we’ll start with you on the clinical trials that led to the approvals of enzalutamide, apalutamide, and darolutamide. What are your thoughts on these trials? Can you give us an overview of all 3 and talk about their primary and survival end points?

Sandy Srinivas, MD: Sure, Alicia. Nonmetastatic CRPC has been a big clinical bucket for us where—with our conventional imaging with bone scan and CT [computed tomography] scans—we’ve never had a drug that resulted in a meaningful end point, such as overall survival [OS]. Knowing the PSA [prostate-specific antigen] height as well as the PSA doubling time in these patients matters.

There were 3 large trials looking at enzalutamide, apalutamide, and darolutamide, all with almost identical trial designs, taking patients with nonmetastatic CRPC defined by conventional imaging and patients whose PSA doubling time was less than 10 months. All 3 trials aimed at showing an improvement in metastasis-free survival [MFS]. Remarkably, the results were almost identical. All 3 trials met the end point of improvement in MFS.

Last year, all 3 trials had a readout of improvement in [OS], which is important in this disease space where patients have no radiographic evidence and no evidence of symptoms. All 3 trials also demonstrated improvement in quality of life. These are compelling. Today, it’s hard to have a patient whose PSA is increasing sit in front of you and to just let them know that we’re going to watch them. It’s remarkable that we have 3 drugs all showing improvement in OS. For that patient with the rapid PSA doubling time, I wouldn’t hesitate to put them on 1 of these 3 drugs.

Alicia K. Morgans, MD, MPH: Thank you for that overview. What a tour de force. That’s a lot of information. I appreciate that. Overall, even for patients in the control arms of all 3 trials who got intensification on progression, they found that earlier intensification led to a survival benefit, which means you cannot make up for that difference in time of earlier intensification. This message seems to be consistent with what we see in metastatic hormone-sensitive disease as well. Earlier intensification brings more bang for our buck.

One thing I’ve heard in conversations in practice is that there can be some confusion. Part of this comes from our imaging, because when we use things like Axumin PET [positron emission tomography], for example, or if we have access to the newer PSMA [prostate-specific membrane antigen] PET studies, we might find patients who, by conventional imaging, don’t have any radiographic evidence of metastatic disease, but on PET imaging, do have areas of metastatic disease. Phil, is this a common thing? Should we expect that these patients are going to have evidence of metastatic disease by PET imaging? How often do you think this might happen?

Phillip J. Koo, MD: Great question. We have some data that shed some light on this. When SPARTAN was first presented, there was another study that looked at a SPARTAN-like population. These patients would have qualified for SPARTAN, and had a PSMA PET-CT performed. In that group, 55% of those patients had M1 disease. Today, the real question is, what do we do with that information, and how does it impact management? I don’t think we know the answer. This is a good example of the potential phenomenon of the Will Rogers effect in this type of patient population.

In instances like this, we need to go back to the data. The PROSPER, SPARTAN, and ARAMIS trials used conventional imaging. Patients who are negative on conventional imaging would qualify for this, because in reality, all these patients who we classify as nonmetastatic probably have micrometastatic disease. It’s always been a limitation of the imaging. Even though the imaging has gotten better, it still can’t detect everything. That’s where we are today. This is another area where, now that we have this better imaging, we can do more research and investigations and have a greater impact.

Alicia K. Morgans, MD, MPH: Great. Thank you. I tend to agree with you. Scott, I’d love to hear your thoughts on that. If you have a patient who appears to have nonmetastatic CRPC on conventional but somehow has PET imaging, either because you ordered it or the patient had it outside of your facility, does a positive PSMA PET change your treatment?

Scott T. Tagawa, MD, MS, FACP: Sometimes. I use the imaging how I want. I agree with Phil. Some might affect the PETs, but if they did, it was ignored. And some allowed some disease limited within the pelvis in the soft tissue. But ignoring that, these patients had nonmetastatic disease by standard cross-sectional imaging and bone scan. Especially those with a short doubling time, I have 0 problem offering any of these agents, whether there’s a PSMA or any other PET that’s positive.

That being said, if there’s a patient who I want to offer sipuleucel-T or something else that requires metastatic disease, I may say, “Hey, they have metastatic disease on this type of imaging.” I use it how I want to use it. But in the setting of relatively low-volume metastatic CRPC, in terms of not a lot of disease on CT, MRI [magnetic resonance imaging], bone scan, and 1 too many metastases on PSMA PET, these patients are appropriate for these drugs. These drugs clearly work in the long run. As Sandy pointed out, they have the overall viewpoint: MFS, OS data, maintenance of patient-reported outcomes despite an AE [adverse effect] rate that’s not 0. It says that these drugs work overall.

Alicia K. Morgans, MD, MPH: Yes, I agree. It’s amazing how consistent these were in terms of their hazard ratios for MFS and OS, even though they’re done with different agents, different studies, and different populations around the globe. It’s impressive and quite consistent.

Transcript Edited for Clarity

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