PSA Responses to Enzalutamide Significantly Associated With Longer MFS in nmCRPC

Maha H.A. Hussain, MD, FACP, FASCO

Nadir prostate-specific antigen (PSA) was found to be significantly associated with metastasis-free survival (MFS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and a rapidly rising PSA who were treated with enzalutamide (Xtandi) in the phase 3 PROSPER trial (NCT02003924), according to Maha H.A. Hussain, MD, FACP, FASCO.

Updated results from the PROSPER trial presented during the 2020 ESMO Virtual Congress showed that by the 17th week of treatment, 79% of men enrolled on the study experienced a PSA decline of 50% or greater from baseline, with 23% demonstrating a PSA value of less than 0.2 ng/mL. These changes were found to be significantly associated with MFS, according Hussain.

Moreover, a PSA decline of 50% or greater, 90% or greater, and to less than 0.2 ng/mL at any time on the study was significantly associated with a 88%, 74%, and 80%, respectively, reduced risk of development of metastasis or death in those who received enzalutamide (all P <.0001). Notably, a PSA decline of 50% or greater demonstrated the strongest prognostic effect versus the other PSA thresholds examined.

“There are 2 things to point out here: For patients, this is reassuring. We’re not bringing the PSA down just because it's a number, but [because it’s] an actual reflection of how their cancer is likely to behave,” said Hussain. “From a physician perspective, hopefully, this [will be] useful to monitor patients. [It helps us to determine] who's getting benefit [from treatment] versus who is not and when to do imaging.”

In an interview with OncLive, Hussain, the Genevieve E. Teuton Professor of Medicine in the Department of Medicine of the Division of Hematology Oncology and the deputy director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine, further discussed the prognostic associations of depth of PSA responses with MFS in patients with nmCRPC and a rapidly rising PSA who have been treated with enzalutamide and other efforts being made in this disease.

OncLive: Could you provide an overview of the evolution of the nmCRPC treatment landscape in recent years?

Hussain: Nonmetastatic CRPC represents a distinct group of patients who clearly have what I would consider to be subclinical cancer, or micrometastatic disease. By conventional imaging, [this disease is] not visible. This is a group of patients who we know have a very rapid doubling time and who, given enough time, will develop metastases. The shorter the doubling time—for example, the PSA going from 1 or 2 to 4—the more likely [a patient] will develop metastatic disease. Up until 2018, this group of patients really had no major, impactful treatment [available to them]. We all used different regimens for them, [including] antiandrogens and steroids; however, none of these treatments have been demonstrated to be life-prolonging.

Three trials were conducted with apalutamide (Erleada), enzalutamide, and darolutamide (Nubeqa). [With these agents], one can actually impact outcomes in terms of delaying the time to metastases. As I tell my patients, an invisible cancer doesn't kill. Therefore, delaying metastases becomes very clinically relevant. Obviously, prolonging survival [is also important], and this has already been seen this year from multiple publications with [the 3 agents].

Could you discuss the design of the phase 3 PROSPER study and the previous data that have read out from it?

The trial that we presented [at the 2020 ESMO Virtual Congress] has been presented previously. This is a phase 3 clinical trial that randomized patients 2:1 to either enzalutamide or placebo. Of course, patients had to be eligible by conventional imaging, organ function, and minimal PSA. At the time of progression, patients were unblinded and were allowed to receive alternative treatments.

The data that we presented at ESMO were specifically looking at if benefit [with enzalutamide can be predicted] at an individual patient level. When we do clinical trials, we're doing them in groups of patients. However, as I tell my patients, each and every [case] is distinct. One cannot assume that just because Mr. Smith experienced benefit [with a treatment] that Mr. Joe is going to benefit, as well. Also, as physicians, we obviously need to be mindful of how often we're going to subject patients to imaging; it has physical and monetary costs.

[This research builds] on data that I published years ago from a phase 3 clinical trial where we looked at the nadir PSA, or the lowest PSA possible, and its association with outcomes in terms of overall survival (OS) and MFS. In the context of metastatic disease, we demonstrated that the PSA going to, and being maintained at, a certain low level can actually predict for better outcomes; that's not a surprise. When a tumor responds, that's better than a tumor that is not responding. Essentially, what we demonstrated here is a similar trend.

What did we see in terms of outcomes by PSA?

I want to begin first by highlighting the clinical trial itself. This is a trial that [enrolled] men who had rising PSA; that was a requirement. Basically, it demonstrated that in this group of patients with rising PSA and negative imaging was that enzalutamide resulted in a significant prolongation of MFS compared with placebo. Similarly, significant prolongation of close to a 1-year difference in OS [was observed]; that's a significant improvement. The time to PSA progression, which is the first flag as it relates to the disease progression, was also significantly longer.

In the trial, all the patients had regular PSA checked and we looked at declines of less than 50%, declines of 90% or greater, or what I would call the Cadillacs of responses, which is an undetectable PSA level of less than 0.2 ng/mL. Then, we looked at these trends and how they correlated with outcomes. Interestingly, a significant percentage of patients who were on the treatment experienced declines of PSA of more than 50%, and this was really very important in terms of early signs.

Also, a significant percentage of patients had PSA [declines] of more than 90%, and a very distinct group of patients achieved undetectable PSA. In fact, the rate of patients who achieved an undetectable PSA was approximately 38%; that's an important sign. More than 85% of patients actually had a PSA decline of 50% or greater, and more than 90% of patients had a 67% decline of PSA. What is clear in terms of the theme is that significant declines of PSA occurred. When we looked at the MFS, we saw significant differences among patients who experienced drops in their PSA. The PSA decline of 50% or greater had a very strong prognostic effect compared with other numbers, partly because we had a higher number of patients who achieved that decline. Essentially, any decline of PSA at any time of the study was significantly associated with significant reduction in the development of metastases.

Based on these findings, where should future research efforts focus?

At the end of the day, we're not curing prostate cancer. What I think is going to be very important to understand is that cure is the ultimate goal. Working toward that, the benchmark is going to be prolonging life and reducing pain and suffering. I feel we have achieved several metrics in that direction. I would hope that in my lifetime we'll be able to achieve not just life prolongation, but actually converting potentially deadly disease, which is the disease setting we're talking about, into at least more of a chronic disease, hoping at some point for a potential cure.

Consequently, a multi-targeted attack strategy against the cancer is going to be significant. Combination treatments are going to be very important. As we say in my old country, you cannot clap with 1 hand, so clearly, we're going to need collaboration and we’re going to need it at multiple levels. [This] includes attacking the cancer with different drugs that can work together [with the same end goal].

What should be taken away from this research?

Effective treatments are important and metrics to judge effectiveness, at the end of the day, cannot just be about a lab value, but also a meaningful effect. The meaningful effect [in this case], is delaying the time to cancer spread, enhancing the response rate, and prolonging life as the ultimate goal. Using what we found, which is something that has been shown in advanced cancer that we have exported into this state of disease, provides a good indication on the potential benefit for an individual patient. This will hopefully help with guiding therapy for the patient and with [disease] management in terms of imaging and other interventions.

From the research perspective, I do believe these types of intermediate end points are important. To do a large study and empower it for OS or MFS takes millions of dollars, thousands of patients, and many years. If you have multiple ideas that you're trying to develop in this setting, such as combination treatments or a new drug, perhaps looking at this intermediate end point as an early metric [will help you to determine] whether the treatment is effective. At the end of the day, we have to do definitive trials; however, this allows for a shortcut to pick the winning horse, so to speak.

Are you involved in other ongoing research efforts that you would like to highlight?

I have been quite fortunate to be involved in quite a few activities. The main focus in my research at this moment is in metastatic, castration-resistant prostate cancer. We're working on potential different projects, 1 trial of which is very near and dear to my heart that we're conducting at multiple centers.

In this investigator-initiated trial, we're looking at the combination of the PARP inhibitor olaparib (Lynparza) with abiraterone acetate (Zytiga), to determine whether 2 are better than 1 or whether 1 is better than the other in patients who have been preselected for having BRCA-like genes. I am a firm believer that no 1 single drug is going to be adequate to cure cancer. This is 1 area that I'm working on.

I'm also collaborating with several of my laboratory colleagues on testing new drugs to see whether some of them will be of benefit. There is a slew of different things that we are working on. Of course, you heard about PROfound, which we just reported on and I think that effort is a major landmark for this disease.

Is there anything else you would like to mention?

I want to extend my personal gratitude to every patient—not just my patients—in the world who is partnering, volunteering, and participating in these clinical trials. Ultimately, what I tell patients and my mentees is that research is what will cure cancer, not wishful thinking. I'm also very grateful to their families and supporters. It does take a village, as they say. We're moving in a dramatic way in this disease compared with when I was in training several decades ago.

Reference

1. Hussain M, Sternberg CN, Efstathiou E, et al. A phase III, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC): Outcomes by prostate-specific antigen (PSA) response. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract: 685P.