(UroToday.com) Radium-223 is a bone-targeted alpha therapy that prolongs survival in patients with symptomatic metastatic castration-resistant prostate cancer (mCRPC) to the bone based on results from the phase III ALSYMPCA trial.1 Docetaxel is a chemotherapy agent that targets microtubule trafficking improving survival in the mCRPC and metastatic hormone-sensitive settings. Previously, it has been determined that the dose and schedule of co-administering Radium-223 + docetaxel in a randomized phase I/IIa trial. The combination appeared to have improved declines in PSA and bone markers, delayed PSA progression, and was better tolerated (with adjusted dose/schedule) relative to standard docetaxel alone.2 The hypothesis for the current study is that simultaneously targeting the tumor and bone compartment yields superior outcomes than targeting either alone. Michael Morris, MD, and colleagues presented the platform for this important phase III study to determine the clinical benefit of the regimen at the 2020 ASCO virtual annual meeting.
Randomization will be 1:1 for 738 men with mCRPC to docetaxel or docetaxel + Radium-223, with a projected hazard ratio for the treatment effect (15 vs 20 months median survival) of 0.75. Patients will receive docetaxel 75 mg/m2 IV every three weeks for 10 doses or docetaxel 60 mg/m2 IV every 3 weeks for 10 doses + Ra-223 55 kBq/kg IV every six weeks for six doses. The trial schema for the phase 3 DORA trial is as follows:
Key inclusion criteria include patients with ≥2 bone lesions, progression by Prostate Cancer Working Group 3 criteria, an Eastern Cooperative Oncology Group performance status of 0-1, and normal organ function. Key exclusion criteria include the use of anticancer therapy ≤4 weeks before randomization, use of bone-seeking radiopharmaceuticals or chemotherapy in the castration-resistant setting, and bulky visceral metastases (≥3 lung and/or liver or a lesion ≥2 cm in the previous eight weeks). The primary endpoint is overall survival, while key secondary and exploratory endpoints include:
- Radiographic progression-free survival
- Symptomatic skeletal event-free survival
- Markers of bone metabolism
- Alterations in circulating tumor cells and DNA
- Detection of androgen-receptor splice variant 7
- Changes in automated bone scan index (aBSI)
- Assessment of patient-reported outcome instruments (FACT-P, Brief Pain Inventory, Brief Fatigue Inventory) between those who received docetaxel and Radium-223
- The number and percentage of febrile neutropenic patients
- The percentage of treatment discontinuation in patients who are on their fourth line of therapy
DORA is open at 28 sites in the US and Netherlands, sponsored by Memorial Sloan Kettering Cancer Center, and managed by the Prostate Cancer Clinical Trials Consortium.
Presented by: Michael J. Morris, MD, Memorial Sloan Kettering Cancer Center, New York, NY
Co-Authors: Ronald De Wit, Nicholas J. Vogelzang, Scott T. Tagawa, Celestia S. Higano; Erasmus MC, Rotterdam, Netherlands; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Weill Cornell Medical College, New York, NY; Fred Hutchinson Cancer Research Center, Seattle, WA
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.
- Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213-223.
- Morris MJ, Loriot Y, Sweeney CJ, et al. Radium-223 in Combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: A Phase 1 Dose-escalation/randomized phase 2a trial. Eur J Cancer 2019 Jun;114:107-116.
Clinical trial information: NCT03574571
View: The DORA Trial, Comparing Overall Survival in Patients Treated with Docetaxel vs. Docetaxel plus Radium-223 - Michael Morris
Read: A Phase III Trial of Docetaxel versus Docetaxel and Radium-223 (Ra-223) in patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC): DORA