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Eur J Cancer. 2019 Jun;114:107-116. doi: 10.1016/j.ejca.2019.04.007. Epub 2019 May 11.

Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase 1 dose escalation/randomised phase 2a trial.

Author information

1
Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA. Electronic address: morrism@mskcc.org.
2
Department of Cancer Medicine, INSERM U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
3
Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
4
Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
5
NorthShore Medical Group, NorthShore University Health System, Evanston Hospital Kellogg Cancer Center, Evanston, IL, USA.
6
The Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
7
Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
8
Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, University of Paris Sud, Villejuif, France.
9
Department of Imaging, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
10
Division of Nuclear Medicine, Department of Radiology, University of Washington, Seattle, WA, USA.
11
Department of Global Clinical Development, Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
12
Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Abstract

PURPOSE:

Radium 223 dichloride (radium-223) is an alpha particle-emitting bone-directed therapy that prolongs overall survival in men with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Docetaxel is an antimicrotubule cytotoxic agent that improves survival in mCRPC. We investigated whether combining these potentially cross-sensitising agents to dually target tumour and bone would be safe and effective.

PATIENTS AND METHODS:

Phase 1 was a dose escalation study to define a recommended phase 2 dose (RP2D) of docetaxel and radium-223. In phase 2a, patients were randomised 2:1 to the recommended combination regimen or docetaxel at a dose of 75 mg/m2 every 3 weeks (q3w). Patients with bone-predominant mCRPC were eligible. End-points were safety, efficacy and treatment-related changes in serum and imaging biomarkers.

RESULTS:

Twenty patients were enrolled in phase 1; 53 patients were randomised in phase 2a: 36 to combination treatment and 17 to docetaxel alone. The RP2D for the combination was radium-223 55 kBq/kg every six weeks × 5 doses, plus docetaxel 60 mg/m2 q3w × 10 doses. Febrile neutropenia was dose limiting. A higher rate of febrile neutropenia was seen in the docetaxel monotherapy arm (15% vs 0%); the safety profile of the treatment groups was otherwise similar. The combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 vs 4.8 months, respectively), alkaline phosphatase (9 vs 7 months) and osteoblastic bone deposition markers.

CONCLUSIONS:

Radium-223 in combination with docetaxel at the RP2D was well tolerated. Exploratory efficacy data suggested enhanced antitumour activity for the combination relative to docetaxel alone. Comparative studies with end-points of clinical benefit are warranted. ClinicalTrials.gov number: NCT01106352.

KEYWORDS:

Castration-resistant prostate cancer; Combination treatment; Docetaxel; Radium 223 dichloride

PMID:
31082669
DOI:
10.1016/j.ejca.2019.04.007
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