Post-Hoc Analysis Provides Quantitative Evidence on Efficacy of Frontline mCRPC Treatments After Progression on Apalutamide

For patients who were progressing to metastatic castration-resistant prostate cancer (mCRPC) from treatment with apalutamide (Erleada) plus androgen deprivation therapy (ADT) in the nonmetastatic setting, progression-free survival (PFS) and overall survival (OS) appeared to be similar irrespective of subsequent treatment choice, according to findings from a post-hoc analysis of the phase 3 SPARTAN trial (NCT01946204).¹

Earlier data from the trial showed that apalutamide plus ADT significantly reduced the risk of metastasis or death vs placebo/ADT in patients with nonmetastatic CRPC (nmCRPC). The median metastasis-free survival (MFS) was 40.5 months in the apalutamide arm vs 16.2 months in the placebo arm (HR, 0.28; 95% CI, 0.23-0.35; P < .0001). Earlier data from the trial supported the February 2018FDA approval of apalutamide in this population.²

The post-hoc analysis was performed in patients from SPARTAN who progressed to mCRPC after treatment with apalutamide plus ADT. These patients received subsequent therapy with either abiraterone acetate (Zytiga), docetaxel, enzalutamide (Xtandi), or other androgen receptor (AR)–targeted agents. Patients in this “Next” cohort displayed a poorer prostate-specific antigen response to apalutamide, as well as worse MFS and OS outcomes compared with the intent-to-treat population from SPARTAN.

Data from the post-hoc analysis presented at the 2023 ASCO Genitourinary Cancers Symposium showed that the median subsequent PFS for all patients in the analysis (n = 311) was 6.8 months (95% CI, 5.8-7.9). Patients treated with subsequent abiraterone plus prednisone (n = 241) had a median subsequent PFS of 6.7 months (95% CI, 5.4-7.8) compared with 7.9 months (95% CI, 5.1-12.1) for those given docetaxel (n = 29), 8.2 months (95% CI, 3.8-14.6) for those treated with enzalutamide (n = 20), and 6.3 months (95% CI, 3.6-15.3) for those given other treatments (n = 21).

The median subsequent OS was 20.0 months (95% CI, 17.0-22.6) for all patients in the post-hoc analysis. The median subsequent OS for the abiraterone/prednisone, docetaxel, enzalutamide, and other groups was 20.2 months (95% CI, 16.7-23.3), 18.2 months (95% CI, 15.7-25.4), 17.0 months (95% CI, 11.1-34.6), and 21.6 months (95% CI, 10.0-25.7), respectively.

“We had the trend that we thought we had to change our treatment’s mechanism of action [by going] from hormonal treatment to chemotherapy, but our results did not show a big difference [between subsequent treatment options],” Boris A. Hadaschik, MD, vice director of the West German Cancer Center Consortium and director and chair of the Department of Urology at Essen University Hospital at the University of Duisburg-Essen, Essen, Germany, said in an interview with OncLive^®.

In the interview, Hadaschik further discussed key results from a post-hoc analysis of subsequent therapy for patients treated on the SPARTAN trial.

OncLive^®: What key data were previously reported from the SPARTAN trial of apalutamide plus ADT in nmCRPC? What inspired the post-hoc analysis?

Hadaschik: The [phase 3] SPARTAN, PROSPER [NCT02003924], and ARAMIS [NCT02200614] trials looked at whether intensified hormonal ablation is of use for men with nmCRPC and a short PSA doubling time. [These trials were done with] conventional imaging, so they started before the era of PET imaging. All 3 trials showed that in men with high-risk disease, the addition of apalutamide to ADT significantly prolonged PFS. [In SPARTAN], the primary end point was MFS on conventional imaging.

[Based on these results], apalutamide is now an FDA-approved therapy [in nmCRPC]. However, the treatment landscape [has changed], and we have so many options for our patients, so it is important to discuss with a patient how we are going to sequence therapies. This was the purpose of the post-hoc analysis within SPARTAN.

We learned that [ADT] intensification in men with a short PSA doubling time makes sense, so this is standard of care. However, [treatment will fail for] many of these men, and the question of subsequent therapy has not properly been addressed.

Please expand on what was examined in the analysis.

Within SPARTAN, we followed patients for PFS2 [after] subsequent therapy lines, [meaning] first-line mCRPC treatment. We also followed the patients for OS. In this presented post-hoc analysis, we can, for the first time, quantitatively look at whether [the choice of] subsequent therapy after progression on apalutamide makes a difference [in outcomes]. This was before the era of combined treatment with an AR-targeted agent and PARP inhibition, and before the era of [lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617)]. So we [only] compared giving another oral AR-targeted agent or chemotherapy.

What is important to note about the patient population included in this post-hoc analysis of the SPARTAN trial and their baseline characteristics?

The SPARTAN trial [included patients] with M0 CRPC on conventional imaging, so it is a somewhat niche indication. Most of the time, these men have had prior therapy, then metachronous [PSA increase], and they have been treated with ADT despite not having metastases. Since the treatment landscape is changing quickly, we have learned that intensifying treatment early on, even in combination with local therapy, is of benefit in this population. ADT will fail some men, but we don’t have metastases on conventional imaging yet. There are men with these disease characteristics that have very long PSA doubling times where you don’t need to intensify [therapy].

In SPARTAN, we chose men with a PSA doubling time [of no more than] 10 months, so these were men at risk of developing metastases and progression. In these men, apalutamide showed benefit.

In this post-hoc analysis, we focused on men in the treatment arm of the SPARTAN study [who] progressed on apalutamide. Men with a [durable] response to apalutamide were not included [in the analysis]. If you look at the different characteristics [for the overall population vs those in the post-hoc analysis], it is a higher-risk population, because fewer men achieved undetectable PSA levels. The MFS and OS of this subgroup was shorter than the whole group of the [apalutamide] arm. The whole group [had a median OS of 73.9 months]; this subgroup we looked at [in the post-hoc analysis had a median OS of 52.8 months]. That is still good for CRPC, but these were somewhat higher-risk men.

What data from the analysis were presented at the 2023 Genitourinary Cancers Symposium?

This population of men were early progressors on apalutamide, so it was a somewhat highest-risk population of men with nmCRPC. In these men, it did not matter if you [switched] to abiraterone or to chemotherapy. Academically, we always think that we must change the mechanism of action. However, in this population of men with poor prognosis, surprisingly, there was not a big difference between chemotherapy and abiraterone [as subsequent therapy].

This supports an earlier observation, where we looked at genetic changes caused by apalutamide. There, we did not see an accumulation of high-risk features [after initial AR-targeted therapy]. It’s reassuring that if we start with apalutamide in the [nmCRPC] setting, we can sequence any therapy afterward.

This [approach applies] for the small subgroup of men with nmCRPC. We are [performing] the same analysis for the positive [phase 3] TITAN trial [NCT02489318] of apalutamide in metastatic hormone-sensitive prostate cancer. [Data from the TITAN post-hoc analysis] will be presented at a later time.

What limitations are important to note regarding this research?

It’s a subgroup analysis and a post-hoc analysis, so we did not [randomly assign] patients following apalutamide to either abiraterone or docetaxel. If you look at the current landscape, [you] might randomize between abiraterone and olaparib [Lynparza], which has an indication in this population, or to give patients a prostate-specific membrane antigen PET and then maybe after docetaxel follow up with [vipivotide tetraxetan]. The [current treatment landscape] is a little bit different; nonetheless, [the post-hoc analysis] is important.

What are the clinical implications of these results?

[These findings] emphasize 2 things. One is that the first intensified treatment line is important. If this treatment is failing, patients have poorer prognosis and an unmet need. We have to improve our therapies, so one agent alone might not be enough. We now have the data for [subsequent therapy following apalutamide], [but] it might be different with other agents.

Editor’s Note: Dr Hadaschik reports serving as a consultant or in an advisory role for ABX Advanced biochemical compounds, Amgen, Astellas Pharma, Bayer, Janssen, Lightpoint medical, Merck KGaA, MSD, Novartis; he received research funding from Bristol Myers Squibb (Inst), Janssen, Novartis (Inst); he has patents, royalties, or other intellectual property from Uromed.

References

1. Oudard S, Hadaschik BA, Antoni L, et al. Efficacy of subsequent treatments in patients who progressed to mCRPC following treatment with apalutamide for nonmetastatic castration-resistant prostate cancer (nmCRPC): A post-hoc analysis of the SPARTAN phase III trial. J Clin Oncol. 2023;41(suppl 6):157.doi:10.1200/JCO.2023.41.6_suppl.157
2. Erleada (apalutamide), a next-generation androgen receptor inhibitor, granted U.S. FDA approval for the treatment of patients with non-metastatic castration-resistant prostate cancer. News release. Janssen. February 14, 2018. Accessed February 28, 2023. https://www.jnj.com/media-center/press-releases/erleada