Comparing PSA Response With Apalutamide vs Enzalutamide in mCSPC

Benjamin H. Lowentritt, MD, FACS

Treatment with apalutamide (Erleada) induced a deeper and earlier prostate-specific antigen (PSA) response compared with enzalutamide (Xtandi) in androgen receptor synthesis inhibitor-naive patients with metastatic castration-sensitive prostate cancer (mCSPC), according to findings from a real-world study.¹

A deep PSA response, defined as a ≥90% PSA decline (PSA90), is a critical treatment goal in mCSPC. This study aimed to compare the PSA90 response rates between apalutamide and enzalutamide in this patient population within the first 6 months of treatment in a real-world setting.

Specifically, by 6 months, a significantly higher proportion of patients treated with apalutamide (n = 860) achieved PSA90 compared with patients given enzalutamide (n = 869; 80.3% vs 75.0%; P =.005). The median time to PSA90 was shorter in the apalutamide arm at 3.5 months vs in the enzalutamide arm at 4.9 months.

“The 6-month timeframe has, for a number of years now, been deemed the critical time element for seeing a PSA response. That is true for prospective randomized trials, and the FDA has determined that this is a really important timeframe to report on because it is not just the depth of response that is important, but also how quickly they get there,” explained Benjamin H. Lowentritt, MD, FACS, in an interview with Targeted Oncology^TM.

In the interview, Lowentritt, medical director of prostate cancer and urologist at Chesapeake Urology in Baltimore, Maryland, discussed findings from this US real-world study.

Targeted Oncology: Can you provide background of this real-world study, including the methods, design, and patient inclusion?

Lowentritt: This is a several-year process, and we have reported earlier data in other meetings looking at this dataset. Initially, there were around 80, and now we are up to close to 100 urology groups who had data in the PPS [Analytics] dataset, where we were able to see a good number of patients that are being treated with metastatic castration-sensitive prostate cancer. For the treatments that we were looking at specifically, there are over 800 patients in each group.

What we have seen is differential responses to some of the more common therapies in use. In this study, we are looking at patients that are receiving apalutamide plus androgen deprivation therapy, and those that are receiving enzalutamide with androgen deprivation therapy, and are able to look at their response, especially in looking at their PSA response. Since this is a discrete number that is usually fairly easily found within the electronic medical record, it allows us to do an analysis in this real-world evidence environment.

Conceptual image for viral etiology of prostate cancer: © Dr_Microbe - stock.adobe.com

What are some of the findings?

What is interesting, and we have seen this in every step of the way, even as the dataset has grown, which has allowed us to feel even more confident with what we are seeing, is that there does appear to be a difference in this PSA response in patients on apalutamide vs those that are on enzalutamide over the course of treatment. Typically, we have to be able to follow these patients out for a year in order for them to be included. But the 6-month timeframe has, for a number of years now, been deemed sort of the critical time element for seeing a PSA response. That is true for prospective randomized trials, and the FDA has determined that this is a really important timeframe to report on because it is not just the depth of response that is important, but also how quickly they get there.

We looked specifically at patients getting at least a 90% reduction in their PSA from prior to treatment, the PSA90, and then we also looked at different time intervals, at 3 months, 6 months, etc. What we found is that there is a more rapid and a more consistently deep PSA response in those patients receiving apalutamide vs those that received enzalutamide. Over the course of the timeframe that we looked at, there was a roughly 20% to 21% difference between the 2 groups as far as how many people responded. I think it is an interesting perspective to have because it really is now a fairly large dataset to be able to look at.

What are the biggest challenges with managing PSA levels in patients with mCSPC?

We have had this back-and-forth discussion about the importance of PSA in patients that have metastatic disease, especially if they are starting to fail treatments in the castrate-resistant disease state. But for patients that are still castration-sensitive, we know that this is still an important marker of, in some respects, a surrogate for long-term outcomes. How we use the PSA becomes a critical component.

It is also fundamentally true that PSA is often the main way that our patients are experiencing their disease. Hopefully these are not patients that are having ongoing symptoms or issues related to their cancer, although with metastatic disease, they could have started out that way. But for many of them, once they are on therapy, and we know that almost all patients will respond to some extent to hormonal therapies like these, it is developing how we can manage their expectations and potentially even start to counsel them differently based on the depth of response that they have.

We talk about both treatment intensification and, in some respects, deintensification. I think it is the patients who are the strong PSA responders that someday we may be able to consider deintensifying their therapy if they have been stable and doing well for a while. I think the PSA number still is relevant. I also think it may impact how frequently we need to monitor these patients. I am certainly less concerned about a patient who has had a deep response to treatment with their PSA and may be able to see them less often, every 3 months vs every 1 to 2 months that I might be seeing for someone that I am worried may be progressing, which is meaningful to patients. I think PSA as a marker remains important. I do not think there are a lot of hurdles to getting it. I think in some respects, in some patients, I am trying to encourage them not to get it so frequently, because they are only developing anxiety every time they get the blood drawn. But I do think that when we start to see good responses, this data, along with a lot of other data that has shown survival benefits, overall survival benefits, progression-free survival benefits, for those patients that have a strong and deep response, can help us better counsel our patients.

From a community oncology perspective, what would guide your decision in choosing apalutamide over enzalutamide as a first-line therapy?

I think this kind of data helps me feel confident that apalutamide would be a strong option for most of our patients. In all fairness, I certainly do not only treat with apalutamide. I use enzalutamide and other agents when appropriate. A lot of times, there might be other reasons, including drug interactions, coverage, and other things that practically can get in the way with some of the treatments. But this kind of data certainly does help me feel confident that for many of my patients, and maybe most of my patients now in this situation, apalutamide can be expected to have the best possible outcome from a PSA response.

Are there any limitations or challenges that might hinder the wider adoption of apalutamide in this space?

Apalutamide has narrower indications than enzalutamide, so I think it is sometimes not first to mind for a lot of providers that are seeing a patient, especially if they do not see that many patients with metastatic castration-sensitive prostate cancer. But I do not see that there is a strong reason that this data could not be used to help guide people towards therapy. For most patients, they should have good access to apalutamide.

What are the next steps for this research?

We have looked at comparisons with multiple other therapies as well, not just between these 2 agents. Certainly, there are other treatment regimens for mCSPC. I think we are looking of broaden the scope of what we are looking at. We have reported previously on comparisons with abiraterone [Zytiga] as well. I think we are going to start looking at patients that may be receiving triplet therapies and others to see if we can get more evidence of the differential response. It is tough because there are always limitations with real-world evidence, and a big thing is trying to make sure we are comparable groups. When you start to look at triplet therapy, we know that those tend to be used in patients with more widespread disease, higher risk disease overall, and we want to make sure that we are controlling for all of that and still able to report on meaningful data. But that is why we are excited to be able to look into those things. It has been multiple years already that we have accumulated this data. Continuing to see this dataset grow, and maybe combining it with others, can get us to real outcomes, and starting to see survival and other types of outcomes for these patients tells an even more complete story, to the extent that we can feel confident doing it with real-world evidence.

REFERENCE:

Lowentritt BH, Du S, Pilon D, et al. Real-world comparison of prostate-specific antigen (PSA) response in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or enzalutamide (ENZ). Presented at the 2024 Genitourinary Cancers Symposium; San Francisco, CA, January 25-27, 2024. Abstract 51.