ASCO 2021: A Phase III Trial of Docetaxel Versus Docetaxel and Radium-223 in Patients With mCRPC: DORA

(UroToday.com) Radium-223 is a bone-targeted alpha therapy and has been shown to prolong survival in patients with symptomatic metastatic castration-resistant prostate cancer (mCRPC) to the bone.¹ Docetaxel targets microtubule trafficking and has been shown to improve survival in both the mCRPC and metastatic hormone-sensitive settings. It has previously been hypothesized that simultaneously targeting the tumor and bone compartment yields superior outcomes than targeting either alone. Morris and colleagues previously determined the dose and schedule of co-administering Radium-223 + docetaxel in a randomized phase I/IIa trial.² The combination arm of Radium-223 + docetaxel had more durable suppression of PSA (median time to progression, 6.6 vs 4.8 months [p=0.020], respectively), alkaline phosphatase (9 vs 7 months) and osteoblastic bone deposition markers:

At the 2021 American Society of Clinical Oncology (ASCO) virtual annual meeting, Dr. Michael Morris and colleagues reviewed the trial design for a phase III study to determine the clinical benefit of docetaxel versus docetaxel and Radium-223 in patients with mCRPC, the DORA trial.

Randomization (1:1) of 738 men with mCRPC to docetaxel or docetaxel + Radium-223 is planned with a projected hazard ratio for the treatment effect (15 vs 20 months median survival) of 0.75. The trial design for DORA is as follows:

Patients with ≥2 bone lesions and progression by Prostate Cancer Working Group 3 criteria are eligible. Other key inclusion criteria are an Eastern Cooperative Oncology Group performance status of 0–1 and normal organ function. Key exclusion criteria are: (i) the use of anticancer therapy ≤4 weeks before randomization, (ii) the use of bone-seeking radiopharmaceuticals or chemotherapy in the castration-resistant setting, and (iii) bulky visceral metastases (≥3 lung and/or liver or a lesion ≥2 cm in the previous 8 weeks).

Subjects receive docetaxel 75 mg/m² IV q3w for 10 doses or docetaxel 60 mg/m² IV q3w for 10 doses + Radium-223 55 kBq/kg IV q6w for 6 doses. The primary endpoint is overall survival. Secondary and exploratory endpoints include:

Radiographic progression-free survival
Symptomatic skeletal event-free survival
Safety
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)

The study is open at 32 sites in the US and Netherlands and has 170 subjects enrolled. As highlighted by the investigators, reasons to participate in this trial are as follows:

For patients with bone metastases and CRPC, the rationale is sound in that you are treating disease systematically with docetaxel and consolidating treatment to bone metastases with radium-223. Furthermore, each arm contains life-prolonging therapy
Most patients with mCRPC will require chemotherapy after androgen receptor targeted agents
Prior docetaxel for mHSPC is allowed
Many protocols require prior therapy with docetaxel for mCRPC, such as numerous arms of the KEYNOTE-365 trial assessing different pembrolizumab combinations

Clinical trial information: NCT03574571

Presented by: Michael J. Morris, MD, Memorial Sloan Kettering Cancer Center, New York, NY

Co-Author: Ronald De Wit, Nicholas J. Vogelzang, Scott T. Tagawa, Celestia S. Higano, Paul Hamberg; Erasmus MC Cancer Institute, Rotterdam, Netherlands; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Weill Cornell Medicine, New York, NY; Fred Hutchinson Cancer Research Center, Seattle, WA; Franciscus Gasthuis & Vlietland, Rotterdam, Netherlands

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021

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