Real-world Evidence Provides More Accurate Representation of Next-generation AR Inhibitor Use and Efficacy in mCSPC

Benjamin H. Lowentritt, MD, FACS

Understanding the real-world use of apalutamide (Erleada), enzalutamide (Xtandi), and abiraterone acetate (Zytiga) for patients with metastatic castration-sensitive prostate cancer (mCSPC) can not only augment clinical trial data to provide a better representation of patients treated in clinical practice but also confirms the attainability of clinical trial outcomes with these agents, according to Benjamin H. Lowentritt, MD, FACS.

According to data from a retrospective study presented at the2023 American Urological Association Annual Meeting, apalutamide administration was associated with higher prostate-specific antigen (PSA) responses, and lower rates of progression to castration resistance vs enzalutamide or abiraterone acetate in patients with mCSPC treated in a community-based urology setting. At 1 year, PSA90 response rates were 72.3% with apalutamide, 61.6% with enzalutamide, and 54.7% with abiraterone acetate. The rates of progression to castration resistance were 33.5%, 38.6% and 44.5%, respectively. Median time to castration resistance was not reached with any androgen receptor signaling inhibitor (ARSI).¹

Outcomes with apalutamide in this study were comparable to those seen in the registrational phase 3 TITAN trial (NCT02489318), which previously led to the agent’s FDA approval for patients with mCSPC in January 2019.In a post-hoc analysis of TITAN, apalutamide reduced the risk of developing castration resistance by 66% vs placebo. Moreover, the median time to castration resistance with placebo was 11.4 months and was not reached with apalutamide.²

“Real-world evidence is a way to [address] some of those questions that might be more specific to our community [practices],” said Lowentritt, who is the director of Minimally Invasive Surgery and Robotics at Chesapeake Urology in Towson, Maryland. “...If we’re looking to understand [whether] there might be a signal that acts differently in the real world, [this type of study] is important, especially [regarding] what we looked at within the apalutamide arm.”

In an interview with OncLive^®, Lowentritt highlighted key findings from the retrospective study of second-generation ARSI use in patients with mCSPC treated in clinic, emphasized the importance of exploring and understanding these data, and discussed several directions for future analyses of real-world outcomes in prostate cancer.

OncLive: Could you discuss the trial design and methodology utilized to evaluate real-world data on PSA response and time to castration resistance in patients with mCSPC initiated on apalutamide, enzalutamide or abiraterone?

Lowentritt: This was a real-world evidence study looking at patients that were put on some of the more recent indications for androgen-receptor [AR] targeted therapy in mCSPC. Through 2018 and 2019, abiraterone, apalutamide and enzalutamide all received FDA approval in that [disease setting]. This study was looking at data extracted from [electronic] medical records [EMR] from 95 urology groups around the country [by] a third-party data mining company. [The company] helped us look at specific end points that we could [identify from] the EMR, specifically PSA response and the depth of response. [On-treatment PSA response was defined as] PSA90, or patients reaching an undetectable PSA that was less than 0.2 [ng/mL] in the common kind of nomenclature. [We] also looked at time to castration resistance. We had to select out many different qualities to find [1739] patients that met the criteria for mCSPC and received [either] apalutamide after its approval date, enzalutamide after its approval date, or abiraterone after its approval. [Patients were] split fairly evenly, [with] a little more than 500 in each group.

What key findings from this retrospective study were reported at the meeting?

A few [results from this study] were interesting. In the cohorts that we looked at, there was a numerically different level of response that favored patients in the apalutamide [cohort] with both PSA90 or undetectable rate, and time to castration resistance. If you look at the curves, that [result is] convincing. It was not necessarily something that we would expect, but it’s real-world evidence showing what’s happening with our patients. More studies have to be designed to take out some of the natural variability between patients. I’m not sure that every patient group could be completely normalized in this type of study. Still, [there was] a clear difference that could be seen [between groups].

Why is it important to evaluate real-world data on outcomes with second-generation AR inhibitors when we already have clinical trial data in this space?

First off, we do have to acknowledge that clinical trials [include] heavily cultivated and very specific types of patients. They don’t necessarily always represent what we see in the real world. Oftentimes, some of these trials are multi-national, and they may under-represent some of the minority populations that are in the US. It’s also hard to expect anyone to do a prospective, randomized, comparative trial for these types of agents.

If you look at the [phase 3] TITAN trial [NCT02489318], which was the registrational trial for [apalutamide’s] mCSPC indication, the rates of PSA90 and the achievement of a PSA less than 0.2 [ng/mL in our study were] very similar to what was seen in [that] trial. It gives us the confidence that we can expect those kinds of results [in our practice]. Even [without officially] comparing [real-world evidence] to anything else, it gives us that ability to say that the trials were indicative of what we can expect.

How might these real-world data affect the selection and use of next-generation AR signaling inhibitors in clinical practice?

[All clinicians] that use these medications end up developing a comfort level with [certain] medications. I still encourage everyone to try and understand [other options]. For those that haven’t tried different medicines and have a limited number of options that they give, I do think it’s worthwhile [to try other approved agents]. You may find that your patients either tolerate one [agent] differently than the other or that you’re happier with the response. Patients may [also] need less dose modifications. That wasn’t something we measured, but that may [occur].

What else might be learned from these real-world outcome data? What remaining questions do you hope to see addressed in the future?

An important part of understanding this kind of [research] is [recognizing how it] opens your eyes a bit more to what’s really available. As we explore more real-world evidence, there’s a lot of questions that we want to ask. [We should also] try to get comparable groups, because this [study] was certainly not [comprised of] heavily matched cohorts. We looked at the patients we could. [There] were fairly even numbers [between cohorts], but we couldn’t stratify for all the different [patient] qualities. There’s more work to be done in parsing this out.

We also have to acknowledge our EMRs, which traditionally have been a black hole for data [that] we haven’t been able to get good things out of. We’re starting to [improve our] approaches to get data [from EMRs] that may actually be meaningful. It behooves us to look at [EMRs] across different groups, states, and patient populations to see if there are some signals that we otherwise wouldn’t be able to pluck out. [We have] an exciting opportunity to explore that, [with the] understanding that there’s always limitations to [interpreting these data].

Were any other presentations at this year’s meeting particularly intriguing or potentially practice-changing within the prostate cancer space?

The [phase 3] EMBARK trial [NCT02319837] was a very interesting trial looking at the use of enzalutamide either with or without androgen deprivation therapy [ADT] vs ADT [alone] for patients [with] high-risk [non-metastatic hormone-sensitive prostate cancer and] biochemical-recurrence. That [study] could [allow] patients that are otherwise [at a] high risk for progression to get earlier intervention. We’ll see how it’s received generally, but I think that’s very exciting information.

What future research in prostate cancer are you looking forward to seeing?

In prostate cancer, [we] continue to be excited about some of the prostate-specific membrane antigen [PSMA]-targeted radioligand therapies and other therapies that are in development. Understanding how we can layer different therapies together, what’s safe, and what opportunities we have [for further combinatorial investigations] is interesting. We’re learning more and more about all the targeted therapies for specific genomic alterations. Talking about PARP inhibition, is that going to be a targeted approach for just specific biomarkers, or is it going to be more of an all-comers approach? People are developing their comfort level [with each approach], and we’ll see how it’s all received.

References

1. Lowentritt B, Du S, Rossi C, et al. Prostate-specific antigen response and time-to-castration resistance among patients with metastatic castration sensitive prostate cancer initiated on apalutamide, enzalutamide, or abiraterone acetate. J Urol. 2023;209(4):e387. doi:10.1097/JU.0000000000003257.14
2. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488