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

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.

Conflict of interest statement

Conflict of interest statement

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.

Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1.

Study profile. (A) Dose escalation scheme.*A return to the very first dose cohort could be considered in the event of 0/3 or 2 docetaxel q3w. If then 2/3 or ≥2/6 DLTs occurred at docetaxel 75 mg/m2, the chosen regimen for the phase 2a cohort was to be radium-223 50 kBq/kg × 5 + docetaxel 60 mg/m2 q3w × 10. (B) Phase 1 dose escalation cohorts. *One patient was replaced, unable to receive both combined doses of radium-223 and docetaxel because of docetaxel hypersensitivity. †Withdrew before receiving both doses of radium-223 to receive another treatment deemed necessary by the study sponsor. ‡Withdrew after receiving both doses of radium-223, too ill to attend the 12-month follow-up visit. (C) Phase 2a safety and efficacy cohort.*25 patients in the combination arm received all planned radium-223 doses, 20 patients in the combination arm and 5 patients in the docetaxel arm received all planned docetaxel doses; the dose for 4 patients in the docetaxel arm was stepped down to 60 mg/m2. The study was completed through 12 months of follow-up from the start of treatment with 23 (70%) patients in the combination arm and 9 (69%) in the docetaxel arm. †Received at least 40% of drug dose, no protocol violation. ¥Including the one patient who was excluded from the per protocol population. †All deaths occurred during follow-up and were due to disease progression. §3 patients entered hospice, and 1 had disease progression. PD, progressive disease; DLT, dose-limiting toxicity; ITT, intention to treat; q3w, every 3 weeks; q6w, every 6 weeks.

Fig. 2.

KaplaneMeier plots for (A) time to PSA progression; (B) time to tALP progression; (C) time to bALP progression and (D) radiographic or clinical progression-free survival. *Per protocol population; intent-to-treat patients who received ≥40% of specified number of radium-223 injections or docetaxel, per dose escalation study results, and have no major protocol violations. †As per Prostate Cancer Working Group 2 (PCWG2). PSA progression for patients with an initial PSA decline from baseline is defined as a PSA increase ≥25% and ≥2 ng/mL above nadir, confirmed ≥3 weeks later; for those with no PSA decline from baseline, progression is defined as a PSA increase ≥25% and ≥2 ng/mL above baseline after 12 weeks. †tALP/bALP progression for patients with an initial decline in tALP/bALP from baseline was defined as a tALP/bALP increase ≥25% above the nadir, confirmed ≥3 weeks later; for patients with no tALP/bALP decline from baseline, progression was defined as a tALP/bALP increase ≥25% above the baseline after 12 weeks. ¥Time to radiographic or clinical progression is a composite end-point encompassing time to first radiographic or clinical progression or death. bALP, bone alkaline phosphatase; CI, confidence interval; PSA, prostate-specific antigen; tALP, total alkaline phosphatase.