The randomized ESCALATE trial has a primary end point of symptomatic skeletal event-free survival.
The first patient has been randomized in the phase 3 ESCALATE trial, which is evaluating combination therapy with the radiopharmaceutical radium 223 dichloride (Xofigo) plus either enzalutamide (Xtandi) or darolutamide (Nubeqa) in patients with metastatic castration-resistant prostate cancer (mCRPC).1,2
The study is specifically comparing the radium-223 combination with a control arm of patients who will receive placebo plus enzalutamide or darolutamide. The targeted enrollment is 500 patients and the primary outcome measure is symptomatic skeletal event-free survival (SSE-FS).
"The eventual outcome analytics may potentially enhance treatment options for mCRPC as patients as well as augment our understanding of advanced prostate cancer sequencing strategies. We are honored to have enrolled and randomized the first subject and are very appreciative of our trial site organization's ongoing commitment," Neal Shore, MD, of Carolina Urologic Research Center, the principal investigator of the trial, stated in a press release.
The ESCALATE trial (NCT04237584) is accruing men aged ≥18 years with progressive mCRPC at screening and on androgen deprivation therapy (ADT). Having at least 2 post metastases and an ECOG performance status of 0 or 1 are also study inclusion criteria. Patients must also be currently receiving ADT with an LHRH agonist or antagonist, or have received bilateral orchiectomy. Unless contraindicated, patients are also required to have received prior treatment with bone health agents (eg, denosumab or zoledronic acid).
Patients are ineligible for the trial if they have small cell carcinoma of the prostate, have received prior chemotherapy for CRPC, or have received prior treatments for mCRPC or CRPC other than sipuleucel-T (Provenge), 5-alpha-reductase inhibitors, estrogens, or older antiandrogens (eg, flutamide, bicalutamide, or nilutamide). Other exclusion criteria include prior radionuclide treatment, prior hemibody or whole-body external radiotherapy, or more than 2 months of prior treatment with abiraterone acetate (Zytiga), apalutamide (Erleada), enzalutamide, or darolutamide. The full list of exclusion criteria is available on the official study site.
The study consists of an initial open-label, 12-week lead-in period in which patients are randomized to receive enzalutamide or darolutamide. After the lead-in, a second, double-blind randomization occurs in which patients are assigned to radium-223 or placebo. Along with radium-223 or placebo, patients will continue to receive the androgen receptor blocker they were assigned to at the first randomization.
The SSE-FS primary outcome measure is a composite outcome measure comprising 4 events that show disease progression: incidence of new symptomatic pathologic bone fractures, the need for orthopedic surgical intervention related to the tumor, the first use of external-beam radiation therapy to relieve skeletal tumor-related symptoms, and new symptomatic spinal cord compression occurring. Secondary end points for the study include overall survival, time to initiation of chemotherapy, radiographic progression-free survival, and safety.
The estimated primary completion date for the trial is September 2024. The study is being sponsored by MANA RBM.
Results from the phase 2 EnzaRadiCate study of enzalutamide with concurrent radium-223 in patients with mCRPC were published in Clinical Genitourinary Cancer in April 2020.3 The analysis included 39 patients with mCRPC and symptomatic bone metastases. Overall, 61.5% of the patients did not have radiographic progression with combinatorial enzalutamide and radium-223, while 38.5% had radiographic progression.
Treatment-related adverse events (AEs) across all grades were reported in 53.8% of patients. The most common all-grade AEs were fatigue (25.6%), nausea (17.9%), and anemia (12.8%). Non–treatment-related serious AEs occurred in 3 patients. There was 1 patient who was hospitalized for sepsis, and disease progression resulted in 2 patient deaths.
Radium-223 is approved by the FDA for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. Darolutamide is approved for the treatment of patients with nonmetastatic CRPC, and enzalutamide has FDA-approved indications for CRPC and metastatic castration-sensitive prostate cancer.
1. NIH US National Library of Medicine: ClinicalTrials.gov. A Study Comparing ARB With Radium-223 vs ARB Therapy With Placebo and the Effect Upon Survival for mCRPC Patients (ESCALATE). Posted January 23, 2020. https://bit.ly/3gS6YU2. Accessed August 12, 2020.
2. Potential Enhancement of Prostate Cancer Treatment Options: First Patient Randomized in Phase III Trial.MANA RBM. Published August 12, 2020. https://prn.to/30RbLQc. Accessed August 12, 2020.
3. Shore ND, Schellhammer PF, Tutrone RF, et al. Open label phase II study of enzalutamide with concurrent administration of radium 223 dichloride in patients with castration-resistant prostate cancer. Clin Genitourin Cancer. 2020;S1558-7673(20)30074-4. doi: 10.1016/j.clgc.2020.02.015.