Looking Beyond PSA Is Key to Understanding Nuances of Prostate Cancer Treatment

Robert Dreicer, MD

Although prostate-specific antigen (PSA) levels have been encompassed into treatment decisions for patients with prostate cancer, understanding the heterogeneity of the disease and the nuances of other factors is important to drive the management of this disease, according to Robert Dreicer, MD.

“[There are] lots of things that we need to work on [in prostate cancer] in terms of developing better understandings at the molecular level to distinguish subsets of patients. Additionally, [we need] better clinical trials that ask which therapy in [a given] setting is the most optimal,” Dreicer said in an interview with OncLive® during the 17th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies.

In the interview, Dreicer discussed the goals of the two presentations he gave during the meeting, explained challenges in treatment decision-making across the prostate cancer spectrum, highlighted case studies that underscored these challenges, and emphasized the need for more comparative evidence in the metastatic castration-resistant prostate cancer (mCRPC) setting.

Dreicer is the deputy director and director of solid tumor oncology in the Division of Hematology/Oncology, and professor of medicine and urology at the University of Virginia Cancer Center in Charlottesville.

OncLive: What was the overall goal of your presentations, “From PSA Failure to Hormone Sensitive Metastatic Prostate Cancer?” and “CRPC: Start of the Art”?

Dreicer: [The goal] was to provide an overview of the complexity of the landscape of prostate cancer. The talk from PSA [failure] to metastatic disease obviously encompasses this huge disease state. I pointed out a couple of cases that are illustrative of the kind of patients who you might see in clinic and some of the issues that we have to think through, [and the presentation] set the stage for some of the more detailed conversations that happened during the meeting, as well as the case-based conference discussions. [My presentation aimed] to point out the heterogeneity of the disease and the heterogeneity of the clinicians who manage the disease, and I tried to put that into context.

The mCRPC setting is also very large, and that discussion was more about what's unique about advanced prostate cancer in that setting compared with other solid tumors. We have very limited data to tell us appropriate [treatment] sequencing [in mCRPC]. There again, [we have to factor in] the heterogeneity of the disease and the heterogeneity of the clinician. If [a patient is] managed by a urologist vs a medical oncologist or a GU medical oncologist, what [treatment] you're offered may differ. In the absence of prospective evidence, that may be okay; however, it's not optimal in terms of how we take care of people.

Can you walk use through a case study you highlighted to help illustrate the heterogeneity of prostate cancer?

One of the cases looked at the context of a patient who presented with locally advanced disease. Locally advanced disease is defined as probably needing multimodality therapy to offer the best potential chance for cure. In the context of using next-generation imaging, or prostate–specific membrane antigen [PSMA] PET CT, findings [for this patient were] suggestive of more distant disease. [Would we] apply curative intent strategies based on how we would historically approach patients, or does the influence of the PSMA PET findings change what we do in the absence of evidence? Remember, none of the trials that we have today, and none of the drugs that are approved, were done in the context of PSMA PET imaging. Therefore, [understanding how to integrate next-generation imaging in treatment decisions] is a real-life, everyday challenge.

What is your typical approach in this type of situation?

First, I understand that the difference in imaging technology is a real issue. Colleagues who've been thoughtful and written about [that difference] suggest that until we have clear evidence to say otherwise, the ability to offer curative-intent therapy should not be altered by subtle findings and imaging. It's one thing to have a PSMA PET that shows extensively distant metastatic disease; however, subtle findings probably shouldn't influence the ability to try to cure those patients with therapy. That may not be a principle, but it is a way of thinking about a problem.

Is there another case that you would like to share?

[Another case examined a patient with] biochemical failure. PSA failure, either post–radical prostatectomy or –radiation therapy, happens commonly, about 30% to 40% of the time. [Biochemical failure is] influenced by not only PSMA PET—which is now increasingly a standard of care—but also new data.

The phase 3 EMBARK trial [NCT02319837] provides evidence of potential benefit from earlier use of either [single-agent] enzalutamide [Xtandi] or enzalutamide in combination with ADT. One of the things that we need to remember is that we’re generally taking men in at least 50 years of age or older and potentially applying more intensive therapy to try to improve outcomes; however, in those settings where we may not be curing patients, we're also exposing people to the risks [associated with] therapies. it's one thing to measure your prostate cancer outcomes, but if you increase cardiovascular risk of mortality, it's harder to say that we should or shouldn’t be doing something. We should at least be more thoughtful because of what might happen. It's easy to think about prostate cancer outcomes, and we have to be more holistic about how we think about intervention in the biochemical failure setting.

Within the mCRPC realm, if a patient is seen first by a medical oncologist, a GU Oncologist, or a urologist, how would you expect treatment approaches to differ?

Expertise is expertise, right? If a patient is seen in a large urology group practice by a clinician in the advanced prostate cancer clinic, he or she is likely to have significant expertise. However, part of [a urologist’s] practice is not typically the use of taxane-based chemotherapy. In a setting in which therapeutics have not been compared [head-to-head] with each other, it may be reasonable for somebody to say, ‘This is a reasonable therapy for you, in part because I don't [offer this other type of treatment], but maybe because there is no evidence of [giving one treatment] would be better than [giving another treatment.]’

If you're a community-based medical oncologist, but you happen to practice near a large urology group practice, you may not see a lot of [patients with] advanced prostate cancer. Therefore, your clinical experience, which may be very large in lung cancer and breast cancer, is less [for prostate cancer], which [might lead to a] less nuanced approach using PSA-driven approaches to therapy as opposed to composite assessment of disease. For urologic medical oncologists, [treating advanced prostate cancer] is part of what we do. Is the care better in a given setting? Not necessarily, but it's likely to be different.

Are there any clinical trials ongoing or planned that could be of importance in the prostate cancer space?

The challenge for us right now in mCRPC is that no therapy is curative. Every therapy that's been approved modestly improved survival. We need new therapies, and the androgen receptor [AR] is the holy grail in this disease. The development of agents in the context of targeting the AR—there may be many different strategies—remains important, because until we begin to truly understand how to move the needle [toward a curative therapy], we need to get a shoulder on a survival curve from a therapeutic intervention.

I don't believe any of the therapies that are in trials right now are going to lead to the kind of paradigm shift we saw recently with [the phase 3] EV-302 trial [(NCT04223856) in first-line urothelial cancer], where enfortumab vedotin-ejfv [Padcev] plus pembrolizumab [Keytruda] improved survival [vs frontline chemotherapy]. We're not going to see that in prostate cancer [right now]. However, we do want to see incremental progress, and many of the novel agents in current trials may hopefully show us that.

You previously mentioned the need for better clinical trials. How might this goal be achieved?

The control arm [in these trials is] we're talking about. One of the great challenges in mCRPC is the use of an alternative AR inhibitor, which we recognize has very limited utility, and in many instances, is no more than a glorified placebo. We need to have active control arms. Frankly, just [improving control arms] would move the needle so that when you look at the National Comprehensive Cancer Network [NCCN] guidelines, you don't see every [treatment option] that's approved listed in one box. The reality is, without [active] comparators, how could you know [which treatment to select?

Regarding the issue I raised earlier [about to type of clinician a patient sees and the impact that has on treatment choice], what happens if drug X, which a particular doctor doesn't give, is a preferred therapy? Then [in that case, the type of treating physician] does matter. More importantly, when a clinician sits with a patient and says, they [would ideally] have level 1 evidence that says 1 treatment is a better in general than [another]. We don't have that [evidence] in advanced prostate cancer. and that's a huge problem.

How user friendly do you find the NCCN guidelines to be for clinicians?

The guidelines don't tell you what to do. They tell you where the evidence is and what is reasonable. The challenge in advanced prostate cancer is that the lack of comparative data doesn't give you the ability to make recommendations for 1 therapy vs another. That's why this disease is so difficult to [manage], and [treatment] is experientially driven. The reality is, experienced clinicians make judgments based on composite assessment and understanding. Clinicians [less experienced with advanced prostate cancer] will say [a treatment] is listed in the NCCN Guidelines, so it's okay to give. That may be true, but that [treatment] may not be optimal.

Prostate cancer is a composite. It's not just PSA. PSA-directed therapy in many clinical settings of prostate cancer is not the only thing to consider. Symptoms, clinical context, and natural history [should also be considered]. PSA is a blessing and a curse in prostate cancer. The curse is that patients understand that a rising PSA is not a good thing. However, we don't treat PSA; we treat patients.