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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 107-116 |
| Number of pages | 10 |
| Journal | European Journal of Cancer |
| Volume | 114 |
| DOIs | |
| State | Published - Jun 2019 |
Bibliographical note
Funding Information:This study was sponsored by Bayer . Medical writing services were provided by Dr. Jim Heighway of Cancer Communications and Consultancy Ltd, Knutsford, United Kingdom, and were funded by Bayer .
Funding Information:
M.J.M. discloses consultancy/advisory roles with Astellas Pharma, Bayer, Endocyte and Advanced Accelerator Applications and has received travel/accommodation expenses from Bayer and Endocyte, and his institution has received research funding from Bayer , Endocyte, Progenics and Sanofi; Y.L. discloses consultancy/advisory roles with Astellas Pharma, AstraZeneca, Janssen, Merck Sharp & Dohme, Pfizer, Roche, Seattle Genetics and Sanofi, and his institution has received research funding from Sanofi; C.J.S. declares stock ownership in relation to Leuchemix, consultancy/advisory roles with Astellas Pharma, AstraZeneca, Bayer, Genentech/Roche, Janssen Biotech, Pfizer and Sanofi and intellectual property interests in relation to Leuchemix and Exelixis, and his institution has received research funding from Astellas Pharma, Bayer , Janssen Biotech, Sanofi and Sotio; K.F. has received honoraria from Bayer and Sanofi, discloses consultancy/advisory roles with Amgen, Astellas Pharma, Bayer, Janssen and Sanofi and has received travel/accommodation expenses from Amgen; C.J.R. has received honoraria from Astellas Pharma, Bayer and Janssen Oncology, discloses consultancy/advisory roles with Bayer, Ferring and Millennium and has received research funding from BIND Biosciences, Karyopharm Therapeutics and Novartis; D.H.S. declares participation in speakers' bureau for Bayer; E.S.A. has received honoraria from Astellas Pharma, AstraZeneca, Clovis Oncology, Dendreon, ESSA, Janssen Biotech, Medivation, Merck and Sanofi, discloses consultancy/advisory roles with Astellas Pharma, AstraZeneca, Clovis Oncology, Dendreon, ESSA, Janssen Biotech, Medivation, Merck and Sanofi, has an intellectual property interest in relation to Qiagen and has received travel/accommodation expenses from Dendreon, Medivation and Sanofi, and his institution has received research funding from Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Clovis Oncology, Constellation Pharmaceuticals, Dendreon, Exelixis, Genentech, Janssen Biotech, Johnson & Johnson, Merck, Millennium, Novartis, Sanofi and Tokai Pharmaceuticals; N.P-.T. has nothing to disclose; D.D. has received travel/accommodation expenses from Bayer Healthcare and General Electric, and her institution has received research funding from Bayer Healthcare ; H.A.J. has received honoraria from Astellas Pharma, Bayer Healthcare and Ipsen and has an intellectual property interest in relation to Cambridge University Press, and her institution has received research funding from GTx and Siemens Healthineers; H.V. discloses a consultancy role with MIM Software, outside the submitted work; O.P. is an employee of Bayer; C.L. is an employee of Bayer and owns company stock; J.A.C. discloses a consultancy/advisory role with Y-mAbs Therapeutics and Bayer and research support from Genentech, Regeneron, Gilead Pharmaceutical and Morphotek; C.S.H. has received honoraria from Genentech, discloses consultancy/advisory roles with Asana BioSciences, Astellas Pharma, Bayer, Blue Earth Diagnostics, Clovis Oncology, Dendreon, Endocyte, Ferring, Myriad Genetics, Orion Corporation and Tolmar Pharmaceuticals, has received travel/accommodation expenses from Asana Biosciences, Astellas Pharma, Bayer , Blue Earth Diagnostics, Clovis Oncology, Dendreon, Endocyte, Ferring, Genentech, Menarini, Orion Pharma GmbH, Myriad Genetics and Pfizer and has an immediate family member who is employed by, has a leadership role in and holds stock in CTI BioPharma, and her institution has received research funding from Aragon Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer , Dendreon, Emergent BioSolutions, Genentech, Medivation, Pfizer and Roche.
Publisher Copyright:
© 2019 The Authors
Keywords
- Castration-resistant prostate cancer
- Combination treatment
- Docetaxel
- Radium 223 dichloride
