Real-world studies compare overall survival between ARPIs in mCSPC

Although androgen receptor pathway inhibitors (ARPIs) are widely used in clinical practice for patients with metastatic castration-sensitive prostate cancer (mCSPC), there are no head-to-head trials comparing their efficacy. This means that treatment selection comes down to patient-specific factors such as comorbidities, potential drug-drug interactions, and other considerations.

Mehmet A. Bilen, MD

To address this unmet need, investigators conducted 2 studies looking at overall survival (OS) outcomes between apalutamide (Erleada) and abiraterone acetate (Zytiga)¹ and between apalutamide (Erleada) and enzalutamide (Xtandi).² Study author Mehmet A. Bilen, MD, recently spoke with Urology Times® about the findings from these studies, expanding on the implications of the results and what questions remain.

He notes that further work is still needed to compare toxicity and tolerability between these agents, as well as to assess outcomes with other options such as darolutamide. As more and more therapies come to market, real-world data such as this will be essential is determining who is the best candidate for each approach, he explained.

Bilen is a GU medical oncologist and the director of the GU medical oncology program at Winship Cancer Institute at Emory University in Atlanta, Georgia.

Urology Times: When choosing between ARPIs in clinical practice, what are some of the factors that guide your decision?

Bilen: The good thing is we have multiple therapy options for our patients. Choosing the right treatment is guided by several factors. Those are patient comorbidities, such as cardiovascular or liver issues, potential drug-drug interactions, [and] the need for concomitant steroids. If someone cannot get steroids, that's an important factor. I think the route and ease of the administration is important. Also, patient preferences, tolerability, quality of life, and insurance coverage are important to make the final decision. All of those shape our therapy selection. Since there is no head-to-head comparison with those agents in a randomized phase 3 clinical trial, real-world studies can be very helpful to inform decision-making.

Urology Times: You and your colleagues recently conducted multiple studies comparing OS between these agents. The first paper looked at apalutamide vs abiraterone. Could you highlight the background and key findings from this analysis?

Bilen: We wanted to address a key clinical gap. No head-to-head clinical trial exists comparing ARPIs in metastatic castration-sensitive prostate cancer, and given the widespread use of both agents, apalutamide and abiraterone, we aimed to evaluate survival outcomes using real-world data.

We found that patients with metastatic castration-sensitive prostate cancer who initiated apalutamide had significantly better overall survival compared to those treated with abiraterone acetate. Specifically, apalutamide was associated with a 26% reduction in risk of mortality at 24 months, which is statistically significant. This benefit persisted if we extended the follow-up with all available data.

This is a large cohort—we had close to 4000 patients included from community-based urology practices across the US. Overall, this highly represents the real-world aspect of prostate cancer. To to have a robust comparison between groups, we also looked and applied inverse probability of treatment weighting, because we wanted to balance the potential confounding factors between the treatment arms. We used the new FDA guidance to conduct this analysis, which set the stage to make the real-world study as robust as possible and [with] as minimal bias as possible, which also strengthens some of our findings from this analysis.

Urology Times: You also conducted a similar study looking at OS between apalutamide and enzalutamide. Could you touch on the background and key findings from that analysis?

Bilen: Just like the other study, both agents, apalutamide and enzalutamide, are guideline endorsed, NCCN [National Comprehensive Cancer Network] recommended first-line therapy options for newly diagnosed patients with metastatic hormone-sensitive [disease,] but we don't have any head-to-head comparison in a phase 3 data. That was our initial reason why we did that study.

We assessed overall survival among patients with metastatic castration-sensitive prostate cancer who receive either apalutamide or enzalutamide. We used the same guidance from FDA, and we used the same methodology in our analysis. We also balanced the main confounding factors such as Gleason score, site of metastases, PSA [prostate-specific antigen], race, age—all the known suspects that affect the outcome.

We found that apalutamide was associated with a significant reduction of death—a 23% reduction at 24 months compared to enzalutamide. We saw that the survival benefit remained consistent over long-term follow-up, with more patients alive at 28 months and beyond. Also, importantly, this cohort included a relatively high proportion of patients from underrepresented groups, with approximately 23% identifying as Black or African American. Overall, these findings add to the growing body of evidence that [shows that] apalutamide may offer a survival advantage in real-world setting in patients with metastatic castration-sensitive prostate cancer.

Urology Times: Looking at these 2 studies together, what are some of the implications of these findings for clinical practice and real-world decision-making?

Bilen: Treating patients is art. Choosing the right medication depends on multiple factors, as I mentioned earlier. Real-world evidence [is] becoming more important in our field, especially as we are using large electronic medical records like AI and other tools help us to conduct those studies as robust as possible. Overall, I think these studies provided important real-world evidence to help guide treatment selection in patients with metastatic castration-sensitive prostate cancer.

Again, all these drugs approved—apalutamide, enzalutamide, and abiraterone—and they are widely used, but there are no randomized phase 3 clinical data compare them head-to-head. These real-world analyses help address this gap by demonstrating a consistent overall survival advantage with apalutamide over both abiraterone and enzalutamide in ARPI-naive metastatic hormone-sensitive prostate cancer. These findings are particularly relevant for clinical decision-making in everyday practice, where patient population are often older, have different comorbidities, [and] have diverse backgrounds. As I mentioned earlier, we had a high proportion of African American patients in these analyses, who are known to be underrepresented in clinical trials. This real-world cohort is similar what we see in our clinical practice.

[All that said,] real-world data also have some limitations. As I mentioned earlier, we used rigorous methodology to balance the non-confounding factors, but there are some factors that we couldn't eliminate that may affect the result of these analyses. Also, treatment adherence, toxicity profiles, and patient reported outcomes are not always available for real-world analyses, which can also affect these outcomes. Hopefully, with advances in technology, we can overcome some of these obstacles in future analyses and use more real-world [data] in clinical practice.

Urology Times: Is there any future work planned based on these studies?

Bilen: We are planning to do some additional subgroup analyses for different patient populations, such as visceral metastases, different comorbidities, and PSA level. We also [want to] look at outcomes [among] different racial and ethnic subgroups, because I think those are very important questions. We are also hoping to do some comparative analyses with darolutamide and other drugs as well.

The toxicity and tolerability are also very important. Hopefully some of our future analyses will factor in the toxicity aspect in addition to survival and other things. Again, I think this is still a growing field, and hopefully we can make these studies as robust as possible.

Urology Times: Are there any ongoing trials or upcoming data in this space that you're particularly excited about?

Bilen: As a GU medical oncologist, things are really heading on the right direction, which is always fun to see and share with my patients. I like having more than 1 option. This gives me more tools when I discuss [options] with my patients and treat their cancer. We have multiple good drugs, and all of those improve overall survival. I think we are pushing the needle in the right direction.

There are number of other large phase 3 trials soon to be reported for patients with metastatic hormone-sensitive prostate cancer. I think ADT [androgen deprivation therapy] and novel hormonal agents will be the backbone of our therapy, but we are [now] asking, should we add another agent as a triplet to that backbone? There is a large clinical trial looking at PARP inhibitors in patients with metastatic hormone-sensitive prostate cancer that are biomarker positive. Hopefully soon we will get results from those studies. There is large phase 3 trial [evaluating] PSMA-RLT in this patient population, in addition to ADT and novel hormonal agent. That's another important trial. There are also other agents such as PTEN inhibitors for biomarker-positive patients. [This disease] can be clinically aggressive, and maybe using biomarker-based approaches will give us an overall survival improvement. Stay tuned. Hopefully next year when we sit down, we’re going to have more data. That also brings [the need for] additional real-world comparison, because more options and more tools means we need to do more real-world [analyses] to guide us how we choose what we choose in our clinical practice.

REFERENCES

1. Lowentritt B, Bilen MA, Khilfeh I, et al. Overall survival in patients with metastatic castration-sensitive prostate cancer treated with apalutamide versus abiraterone acetate: a head-to-head analysis of real-world patients in the USA. J Comp Eff Res. 2025:e250023. doi:10.57264/cer-2025-0023

2. Bilen MA, Lowentritt B, Khilfeh I, et al. Overall survival with apalutamide versus enzalutamide in metastatic castration-sensitive prostate cancer. Adv Ther. 2025 May 29. doi:10.1007/s12325-025-03207-6