ASCO GU 2021: Overall Survival and Metastasis-Free Survival by Depth of PSA Decline in the Phase III PROSPER Trial of Men With nmCRPC Treated with Enzalutamide

( There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in nmCRPC 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 (MFS). Subsequently, further follow-up of SPARTAN, PROSPER, and ARAMIS has demonstrated a significant improvement in overall survival as well. Previous post-hoc analyses of PROSPER have demonstrated longer MFS among patients who have greater PSA decline and increased risk of metastases among those with PSA progression. To provide guidance on expected outcomes and explore the influence of PSA dynamics further, in a plenary abstract presentation in the Poster Highlights Session: Prostate Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Hussain and colleagues presented an analysis of overall survival and metastasis-free survival among patients in the PROSPER trial according to the depth of PSA response.

The methodology of the PROSPER trial has previously been reported and published. In brief, men with nmCRPC, PSA doubling time ≤ 10 months, and PSA ≥ 2 ng/mL at screening were randomized in a 2:1 fashion to enzalutamide 160mg or placebo, in addition to continuing androgen deprivation therapy. 

Given the primary outcome, as previously reported, of metastasis-free survival, assessment of overall survival was assessed as a key secondary outcome utilizing a group sequential testing procedure with O’Brien-Fleming-type alpha spending function. In this post-hoc analysis, the authors stratified patients into four groups on the basis of the level of PSA decline at nadir: <50% (referent), 50-90%, 90% or greater with nadir ≥ 0.2 ng/mL, 90% or greater with nadir <0.2 ng/mL. The authors used unstratified Cox proportional hazards analysis models to assess overall survival and MFS between these four groups.

Among 1,401 men enrolled in PROSPER and 933 who were treated with ENZA, PSA data were available for 905 men.

At nadir, 38% of men achieved PSA reduction ≥ 90% (actual nadir < 0.2 ng/mL), and another 27% achieved PSA reduction ≥ 90% (actual nadir ≥ 0.2 ng/mL). Among men in the placebo arm of PROSPER, only 3/457 reported PSA reduction ≥ 90%.
As demonstrated below, the depth of PSA response at nadir was strongly associated with overall survival and metastasis-free survival, with a dose-response relationship.

The authors, therefore, conclude that, among patients in the PROSPER trial receiving enzalutamide, the degree of PSA response is strongly associated with survival outcomes.

Presented by: Maha H. A. Hussain, MD, FACP, FASCO, is the Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine, and the Deputy Director at the Robert H. Lurie Comprehensive Cancer Center of the Northwestern University Feinberg School of Medicine in Chicago, IL.

Co-Authors: Cora N. Sternberg, Eleni Efstathiou, Karim Fizazi, Qi Shen, Xun Lin, Jennifer Sugg, Joyce Leta Steinberg, Bettina Noerby, Ugo De Giorgi, Neal D. Shore, Fred Saad

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Twitter @WallisCJD during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021