The Future of Nonmetastatic CRPC Management

Transcript: Alicia Morgans, MD, MPH: The future of nonmetastatic CRPC [castration-resistant prostate cancer] is a little murky, from my perspective, because of the imaging issues that we’re going to have. There are some practitioners who don’t treat biochemical recurrent disease until patients develop metastasis. Though hopefully that group of people will shrink when they realize that if they have high-risk patients with nonmetastatic biochemical recurrent disease, they can treat them and prolong the time to metastasis-free survival when they become nonmetastatic castration-resistant. But the novel imaging techniques that we have are detecting metastases that we don’t really know what to do with, and the data are all performed around these older scans that don’t necessarily detect metastases while the novel imaging does.

The future holds a bit of a question mark for nonmetastatic CRPC. We may find that it’s a disappearing population of patients, but I hope these drugs remain in circulation and practice because the drugs certainly help patients. It’s just a matter of us understanding which population. As the population shifts, hopefully we can shift and continue to use the agents that will help them, just with new data and a new understanding of how that will work.

The landscape of treatment for nonmetastatic CRPC is changing because we have 3 options now. We really can talk with our patients about choosing the best agent. We have a nice set of choices. It’s also changing because of imaging. As novel imaging becomes more commonly used, we’re going to detect metastases earlier, when they’re very, very small and certainly undetectable by conventional imaging, as the definition would suggest. As we continue to move forward and detect these metastases, and clinicians and patients feel the need to do something more, I think the landscape will change. Hopefully we’ll still have access to these agents. We’ll have to define them as maybe not metastatic but metastatic by novel imaging and try to wrap our heads around what that means.

Elizabeth Heath, MD: It’s a tough space. In some sense, the nonmetastatic castration-resistant space is shrinking. It’s shrinking because we have better imaging tools. A lot of this, in terms of the entry point, including in ARCHES, you have your standard CT [computed tomography] scan and bone scan to say whether you actually have metastatic disease or not. Well, if you don’t see it in those traditional means, then yes, you have no visible cancer. You just have PSA [prostate-specific antigen] as a gauge. But we now have newer PET [positron emission tomography] scans, be it the Axumin [fluciclovine F 18] scans or other ones in development. You can really track very small, fine points of where the cancer may be. So those folks were not technically included. They may have been, based on their radiological studies that were done, but that’s an emerging space that might all of a sudden sort of make the nonmetastatic group disappear.

One would hope for that with technology development that might happen. It’s already starting to happen. But who knows what that really means, because all 3 of these trials did the right thing. They defined the patient group that they were looking at based on specific imaging criteria. And then, also in the follow-up, everyone got their scans at the same time point—at 16 weeks. So there’s some uniformity. There’s no, “Did you get worse in between? What were you when you started?” There is some uniformity. That’s really important.

And then I think emerging drugs—it’s sort of what exists in the castration-resistant metastatic space. We’re in the world of genetics and genomics. PARP inhibitors are alive and well, and undoubtedly will make their way earlier into our disease space. That will be interesting as it evolves, as we’re now doing standard germline testing for metastatic prostate patients, high-risk patients. And then, also, genomic testing, so more in the somatic testing range. We’ll see what happens, but that will impact how we develop drugs in this space in the future.

Alicia Morgans, MD, MPH: My advice for clinicians who are treating nonmetastatic CRPC would be that, at this point, even if you have a novel imaging technique—like an Axumin scan or a PSMA [prostate-specific membrane antigen] scan that suggests that there’s metastatic disease—if standard imaging is negative, these are nonmetastatic patients as we defined them in the clinical trials PROSPER, SPARTAN, and ARAMIS. Because they are, by that definition, fitting the criteria of these clinical trials, they can benefit from these treatments. I would suggest that even if you find what you believe is metastases on these novel modalities of imaging, use the drugs that we know work in these patients to prevent that end point of metastasis-free survival. It does look as though they help patients feel well. It certainly prevents detectable metastases by conventional imaging, and that I think helps our patients.

Matthew R. Smith, MD, PhD: Apalutamide was the first drug approved, with the primary end point of metastasis-free survival. Subsequently, enzalutamide and darolutamide were also approved using that same primary end point in nonmetastatic castration-resistant prostate cancer. It’s also worth noting, as a historical footnote, that these are the first drugs approved in any setting in oncology based on metastasis-free survival. In prostate cancer we have a special leg up, because we have this robust biomarker called PSA that allows us to identify patients who are progressing by a blood test prior to progressing by standard radiographic imaging. I think there’s widespread acceptance of this as an important end point in prostate cancer. The approval of these 3 drugs, I believe, is supported by the clinical importance of metastasis-free survival, as well as the very large treatment effect and consistency of results across different subgroups.

Transcript Edited for Clarity