An analysis of a pair of large-scale studies of apalutamide (Erleada) in patients with prostate cancer showed positive results for survival and reduced disease progression based on high prostate-specific antigen (PSA) responses. These observations were corroborated by a real-world study of apalutamide in these patients, which showed similar high PSA responses as well as strong treatment adherence by patients.
The phase 3 TITAN (NCT02489318) and SPARTAN (NCT01946204) trials evaluated the addition of apalutamide to androgen deprivation therapy (ADT); TITAN included patients with metastatic castration-sensitive prostate cancer (mCSPC) while SPARTAN include patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Patients received 240 mg of apalutamide a day orally.
Kim Chi, MD, discussed an analysis of both trials in an oral presentation at the American Urology Association annual meeting.1 The analysis observed that in both trials, a PSA response of 90% was achieved in a majority of patients; 72% in TITAN and 62% in SPARTAN.2,3 Patients who received apalutamide were found to have a higher rate of radiological progression-free survival (rPFS) than those who only received ADT.
A real-world study by Benjamin Lowentritt of 63 United States urology practices who administered apalutamide found a 50% or more decline from baseline PSA response rates.4 Patients also demonstrated a high rate of adherence, indicating that the treatment was well tolerated.
Neeraj Agarwal, MD, a professor of medicine and director of the genital urinary oncology program at the Huntsman Cancer Institute at the University of Utah, and a co-author of Dr Chi’s analysis, spoke with Targeted OncologyTM about the success of the TITAN and SPARTAN studies as well as its use in real-world prostate cancer populations.
TARGETED ONCOLOGY: Could you discuss what your analysis shows about the TITAN and SPARTAN trials and their efficacy?
AGARWAL: The phase 3 TITAN and SPARTAN studies were large studies conducted in men with mCSPC and patients with nmCRPC, respectively.2,3 We also know that PSA responses are PSA values. When we treat our patients with any ADT plus/minus intensification, the PSA values are very meaningful to us and to our patients, and they provide an easy measure to evaluate our patients.
What were the methods of this analysis looking at PSA response?
What we did in this analysis was to look for the degree of PSA responses and correlation of PSA responses with survival outcomes.1 The PSA decrease of 90% is a validated way to assess PSA response or undetectable PSA, which is PSA of less than 0.2 ng/mL. They were considered standard measures of PSA responses in our study. Patients in both studies, TITAN and SPARTAN, when they had a PSA 90% response or PSA of less than 0.2 ng/mL, we correlated these responses with survival outcomes.
Please discuss the results found by you and your fellow investigators.
We included 525 patients from the TITAN study who underwent treatment with apalutamide, and we included 806 patients from the SPARTAN study, so all patients in TITAN and in SPARTAN who had treatment with apalutamide. Let's look at the PSA 90% responses first. The majority of patients in the TITAN study, 72% of patients, achieved a PSA 90% response, which is remarkable. Even in the SPARTAN trial, which was a CRPC population—meaning these patients already had disease progression on ADT—62% of patients achieved a PSA 90% response.
If you look at undetectable PSA rates in the TITAN study, 67% of patients achieved undetectable PSA rates. In the SPARTAN study, 38% of patients achieved undetectable PSA responses.
Let's see how these PSA responses correlated with survival outcomes. Progression-free survival in the context of the TITAN study was a rPFS, and in the context of SPARTAN it was metastasis-free survival, and both are surrogates for overall survival.
In the TITAN study, 90% PSA responses were associated with a [54%] reduction in risk of [progression]. In the SPARTAN study, 90% PSA responses were associated with [64%] reduction in risk of disease progression.
Let's look at the PSA undetectable rates and how they correlated with overall survival outcomes. If we look at the PSA undetectable rate in either the TITAN or SPARTAN trial, both were associated with more than 80% reduction in risk of death when compared to those patients who did not achieve undetectable PSA.
What are the key takeaways from the TITAN and SPARTAN trials according to your analysis?
In the TITAN study, 67% of patients achieved undetectable PSA. In the SPARTAN study, 38% of patients achieved undetectable PSA rates. In both cases, if you achieved an undetectable PSA, you had patients who are likely to have or have experienced 80% reduction in risk of death. So again, these are striking findings, in my view, that tell me about the efficacy of apalutamide in our patients with mCSPC and nmCRPC.
What we saw was that the combination of apalutamide with ADT demonstrated deep and durable PSA decline, and most of them happened pretty rapidly within 3 months. The faster time to deeper PSA decline was associated with longer survival. These data, in my view, would be very useful to guide monitoring decisions for our patients in clinical practice, and establish PSA end points for future clinical trials.
Do the results of these studies align with real-world outcomes?
I'd like to bring your attention to a real-world study presented by Dr Benjamin Lowentritt in the American Urology Association 2021 annual meeting in another oral presentation.4 In this study, Dr Lowentritt presented the data from a real-world patient population of nmCRPC who were treated with apalutamide. PSA response in this study was defined as a PSA response of 50% or more.
What Dr Lowentritt showed was really reflective of what we presented from the TITAN and the SPARTAN studies. PSA responses were present in the vast majority of patients, around 86% of patients in this real-world setting, and remarkably, the adherence rates are very high. If you look at the adherence [rate] with apalutamide over this period, 93.6% of patients were adherent to the treatment with apalutamide. In a real-world patient population, it seems like apalutamide is associated with high PSA responses and seems to be well tolerated as evidenced by the high adherence rate.
Overall, in my view, these data from 2 different presentations are quite compelling and show that treatment with apalutamide in patients with mCSPC or nmCRPC was associated with deep PSA responses, which occurred early on during the course of treatment. They were associated with significant improved survival outcomes compared with those patients who did not achieve these responses.
1. Chi KN, Saad F, Chowdhury S, et al. PD34-11 Prostate-specific antigen kinetics in patients with advanced prostate cancer treated with apalutamide: results from the TITAN and SPARTAN studies. J Urol. 2021;206(suppl 3):e587. doi:10.1097/JU.0000000000002038.11
2. Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546
3. Chi KN, Agarwal N, Bjartell A, et al; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307
4. Lowentritt B, Brown G, Kernen K, et al. PD05-08 Real-world effectiveness and treatment adherence of apalutamide in non-metastatic castration-resistant prostate cancer patients. J Urol. 2021;206(suppl 3):e58. doi:10.1097/JU.0000000000001969.08