Final results of Alliance A031902: A phase III trial of enzalutamide plus rucaparib as first-line therapy in metastatic castration-resistant prostate cancer (CASPAR).
Abstract
5069 Background: Inhibition of androgen receptor (AR)-signaling results in increases in double-strand DNA breaks and genomic instability. PARP inhibitors (PARPi) are a standard treatment option for patients (pts) with homologous recombination repair mutations (HRRm). Combinations of PARPi and AR pathway inhibitors (ARPI) are associated with synthetic lethality in multiple pre-clinical studies. Clinical trials have suggested potential benefits with co-targeting PARPi and ARPI in pts with and without HRRm. Methods: Alliance A031902 compared radiographic progression-free survival (rPFS) and overall survival (OS) as co-primary endpoints with enzalutamide and rucaparib (Enz/Ruca) versus enzalutamide plus placebo (Enz/Plac) for pts with metastatic castration resistant prostate cancer (mCRPC) regardless of BRCA/HRRm status. This trial was conducted by the Alliance for Clinical Trials in Oncology in 36 centers in the US. Target sample size was 1,002 patients. Eligibility required mCRPC with or without measurable metastatic disease and was agnostic regarding HRRm status. The trial was discontinued in 10/2023 due to changes in the treatment landscape for this pt population. Results: Between 10/21 and 4/23, 61 pts were randomized to Enz/Ruca (n=30) or Enz/Plac (n=31). Known BRCA1/2 or PALB2 mutations were present in 1 pt (3.3%) in the Enz/Ruca arm and 1 pt (3.2%) in the Enz/Plac arm; wildtype in 14 (46.7%) vs 15 (48.4%), and unknown in 15 (50%) vs 15 (48.4%), respectively. Three patients (11.5%) in the Enz/Ruca arm discontinued due to an adverse event (AE) vs 0 in the Enz/Plac arm. Among response-evaluable pts, 7/26 (27%) in the Enz/Ruca arm discontinued due to disease progression vs 10/31 (33%) in the Enz/Plac arm. Most common grade 3+ AEs were anemia (33% vs 3%) and hypertension (17% vs 10%) in the Enz/Ruca arm and Enz/Plac arm, respectively. All 61 pts were evaluable for response assessment. PSA declines ≥50% and ≥90% were observed in 79% vs 45% and 60% vs 43% of pts receiving Enz/Ruca versus Enz/Plac, respectively. Median PFS in the Enz/Ruca vs Enz/Plac arms was 17.1 vs 14.2 mos, respectively (HR 1.13 [95% CI: 0.42-3.01], p=0.81), median rPFS (inclusive of unequivocal clinical progression) was 17.1 vs 11.7 mos ( HR 0.72; 95% CI: 0.31-1.67, p = 0.44), and median OS was not reached vs 27.0 mos (HR 0.65; 95% CI: 0.29-1.45, p=0.29). Conclusions: In this prematurely terminated phase III study, Enz/Ruca was generally well tolerated, with the safety profile consistent with prior PARPi/ARPI combinations. Efficacy outcomes for rPFS and OS are inconclusive due to limited sample size. Definitive conclusions regarding the clinical benefit of this combination cannot be determined from this study. Clinical trial information: NCT04455750 .
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (17)
Charles J. Ryan
Memorial Sloan Kettering Cancer Center, New York, NY
David W. Hillman
Alliance Statistics and Data Center, Mayo Clinic Rochester, Rochester, MN
Karla V. Ballman
From the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda (A.B.A., N.S., S.N., L.L., L.C.), the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (J.H.-C.), and the Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Rockville (H.S., E.S.) — all in Maryland; the Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN (K.V.B., M.O., C.M., G.P.B.); AdventHealth Cancer Institute and the University of Central Florida, Orlando (G.S.); Dana–Farber/Harvard Cancer Center, Boston (S.B., B.M.); UNC Lineberger Comprehensive Cancer Center, Chapel Hill (W.Y.K.), and Duke University Medical Center and Duke Cancer Institute, Durham (J.H., S.H.) — both in North Carolina; the University of Kansas Cancer Center, Westwood (R.P.); Memorial Sloan Kettering Cancer Center, New York (M.Y.T., M.J.M., J.E.R.), and Roswell Park Comprehensive Cancer Center, Buffalo (G.C.) — both in...
Alan Tan
From the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda (A.B.A., N.S., S.N., L.L., L.C.), the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (J.H.-C.), and the Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Rockville (H.S., E.S.) — all in Maryland; the Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN (K.V.B., M.O., C.M., G.P.B.); AdventHealth Cancer Institute and the University of Central Florida, Orlando (G.S.); Dana–Farber/Harvard Cancer Center, Boston (S.B., B.M.); UNC Lineberger Comprehensive Cancer Center, Chapel Hill (W.Y.K.), and Duke University Medical Center and Duke Cancer Institute, Durham (J.H., S.H.) — both in North Carolina; the University of Kansas Cancer Center, Westwood (R.P.); Memorial Sloan Kettering Cancer Center, New York (M.Y.T., M.J.M., J.E.R.), and Roswell Park Comprehensive Cancer Center, Buffalo (G.C.) — both in...
Manish Kohli
University of Utah, Salt Lake City, UT
Pedro C. Barata
Division of Solid Tumor Oncology, Department of Medicine University Hospitals, Cleveland Medical Center Case Western Reserve University School of Medicine Cleveland Ohio USA
Benjamin Gartrell
Department of Oncology, Montefiore Einstein Comprehensive Cancer Center, Bronx, NY
Robert Grubb
Medical University of South Carolina, Charleston, SC
David James VanderWeele
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
Ronald C. Chen
University of Kansas Medical Center, Kansas City, KS
Lionel D. Lewis
Dartmouth Cancer Center, Lebanon, NH
Cecilia Voss
Mayo Clinic Rochester, Rochester, MN
Scott T. Tagawa
Weill Cornell Medical Center, NewYork Presbyterian Hospital, New York, NY
Arpit Rao
Himisha Beltran
Rana R. McKay
Department of Medicine, Urology, and Radiation Medicine and Applied Sciences University of California‐San Diego La Jolla California USA
Michael J. Morris
Department of Medicine, Memorial Sloan Kettering Cancer Center