Biomarkers of apalutamide response identified in nonmetastatic CRPC
medwireNews: Further analysis of patients with nonmetastatic castration-resistant prostate cancer (CRPC) from the SPARTAN trial has identified molecular biomarkers associated with long-term responses to apalutamide.
Speaking to delegates at the 2021 Genitourinary Cancers Symposium, Felix Feng (University of California, San Francisco, USA) explained that the SPARTAN trial, reported previously by medwireNews, demonstrated a significant metastasis-free survival and overall survival benefit with the addition of apalutamide rather than placebo to androgen deprivation therapy (ADT).
To investigate potential biologic signatures of response to apalutamide, Feng and colleagues stratified the 233 participants with available archival tumor samples (ie, the biomarker cohort) into quartiles, based on the number and timing of metastatic events.
Patients without progression and those who had a metastatic event in the fourth quartile were considered long-term responders, with a median time to metastatic progression of 40.5 and 22.0 months in the apalutamide and placebo groups, respectively. By contrast, participants who had a metastatic event in the first quartile were deemed early progressors and had corresponding median times to progression of 7.3 and 3.6 months.
The researchers generated gene expression profiles from tumor samples and identified predefined gene signatures indicative of prostate cancer biology that were differentially expressed between long-term responders and early progressors and had a treatment-specific effect on clinical outcomes. These signatures were considered potential predictive biomarkers of response to apalutamide.
Among apalutamide-treated patients, baseline molecular signatures indicative of increased immune activity, decreased tumor vascularization, or decreased proliferative capacity were each associated with long-term response to the drug. None of these signatures correlated with long-term response in the placebo group; instead, molecular signatures indicative of increased hormonal independence and metastatic capacity were linked to early progression in this cohort.
Feng highlighted the association between increased baseline expression of signatures suggestive of T-cell proliferation, specifically interleukin (IL)-2 signaling, and improved metastasis-free survival following apalutamide treatment, which indicates the utility of IL-2 signatures as “a predictive rather than prognostic biomarker.”
The presenter concluded that “[a]lthough the data require confirmation in larger studies, these molecular determinants may have utility in selecting [patients] with [nonmetastatic] CRPC who may derive the most benefit from [apalutamide] and other androgen signaling inhibitors.”
Discussant Joshi Alumkal (University of Michigan Rogel Cancer Center, Ann Arbor, USA) pointed out the small sample size of the biomarker cohort, and therefore proposed validating these results using samples from patients in the ARAMIS or PROSPER trials of other androgen receptor antagonists.
Highlighting that overall survival was not examined in the current analysis, Alumkal added that “it is important to know whether this signature showed consistency across endpoints, including for overall survival.”
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