ASCO GU 2021: Molecular Determinants Associated with Long-Term Response to Apalutamide in Nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC)

( There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in non-metastatic castration-resistant prostate cancer, at GU ASCO in February 2018, there were no specifically approved treatment options for these patients. These agents, as well as darolutamide (on the basis of data from ARAMIS), were subsequently approved on the basis of demonstrated improvements in metastasis-free survival. In a plenary abstract presentation in the Oral Abstract Session: Prostate Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Felix Feng provided an exploratory analysis investigating potential biological signatures of patients with long-term responses.

The methodology of the SPARTAN trial has been previously described in both presentations and publications. In short, 1207 patients with non-metastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of ≤ 10 months were randomized in a 2:1 fashion to apalutamide 240mg daily or placebo, in addition to continuing androgen deprivation therapy. As previously published, SPARTAN demonstrated a significant improvement in metastasis-free survival and in overall survival.


Among the SPARTAN cohort, the authors defined a biomarker subset and classified these as long-term responders (LTR) or early progressors (EP) based on their time to metastasis based on quartiles, stratified by randomization into the apalutamide and placebo groups. Patients in the first quartile of time to metastasis (i.e. shortest time) (apalutamide, 21; placebo, 17), were classified as EP. In contrast, those progressing in the last quartile (i.e. longest time) (apalutamide, 39; placebo, 20) were classified as LTR.


Using 233 archival primary prostate cancer specimens, gene expression profiles were generated and predefined gene signatures indicative of cancer biology were compared between LTR and EP groups, stratified within the apalutamide and placebo arms.


Dr. Feng emphasized that baseline characteristics were similar between patients in the biomarker cohort and the overall ITT population. Regardless of biomarker status, patients derived clinical benefit from the use of apalutamide. Notably, within the biomarker cohort, baseline characteristics were similar between EP and LTR patients, within each treatment arm.

In the LTR group, the median time to metastatic progression was 40.5 months among patients receiving apalutamide and 22 months in those receiving placebo. In contrast, in the EP group, the median time to metastasis was 7.3 and 3.6 months in patients receiving apalutamide and placebo, respectively.

The authors classified gene signatures into 3 general mechanistic classes (immune regulation, proliferation, and hormone dependence) which were associated with LTR among patients receiving apalutamide. In particular, these included increased T cell activity reflected by T cell activation (p = 0.0045), stimulation (p = 0.0642), cytokine response (p = 0.0489), and interferon production (gamma response p = 0.0227), and decreased T cell exclusion (p = 0.0652), low proliferative capacity (p = 0.0435), and increased hormonal dependence (p = 0.0485). Among patients receiving placebo, early progression was associated with high risk (DECIPHER p = 0.0406, metastatic potential p = 0.0077), hormone nonresponsive (basal p = 0.0115; androgen receptor activity-low, p = 0.0437), and neuroendocrine-like tumors (p = 0.0125).


Further, patients with evidence of T cell proliferation demonstrated longer MFS when receiving apalutamide + placebo, as compared to those with low T cell profiles. However, this wasn’t seen in patients receiving placebo, suggesting this is a predictive rather than prognostic biomarker.


Using previously described signatures based on basal vs luminal subtype, Dr. Feng and colleagues found that those with luminal subtypes have a more favourable prognosis. However, patients with a basal phenotype and a T cell high signature have a similarly favourable outcome while those with a basal phenotype and a T cell low signature have a poor prognosis.


In conclusion, the authors have identified molecular signatures which may allow for the selection of patients most likely to benefit from apalutamide in nmCRPC, though these results require further validation.

Presented by: Felix Y. Feng, MD, Professor of Radiation Oncology; Urology; and Medicine, Vice Chair for Faculty Development and Director of Translational Research, Department of Radiation Oncology,  and Director of the Benioff Institute for Prostate Cancer Research at the University of California of San Francisco

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021