Urologic Oncology: Seminars and Original Investigations
Original articleA multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: A department of defense prostate cancer clinical trials consortium study
Introduction
Metastatic castration-resistant prostate cancer (mCRPC) is the fifth leading cause of cancer death among men worldwide, with an estimated 307,000 deaths in 2012 [1]. Taxane-based chemotherapy remains a cornerstone of treatment for advanced prostate cancer. In contrast to the substantial survival benefit observed with taxane-based chemotherapy in the metastatic hormone-sensitive setting [2], treatment with single-agent docetaxel in mCRPC has demonstrated only a modest survival benefit compared to older chemotherapeutic regimens such as mitoxantrone [3]. Additionally, multiple attempts to combine docetaxel with investigational agents have failed to improve survival compared to docetaxel monotherapy [4], [5], [6], [7], [8], [9], [10], [11]. Thus, new combination treatment approaches, including potentially combining agents with proven single-agent activity, are needed to improve outcomes with front-line chemotherapy in mCRPC.
Cabazitaxel is a semisynthetic taxane derivative that has significant antitumor activity in mCRPC at both the 25 and 20 mg/m2 dose levels, with the former approved for use in mCRPC that has progressed on prior docetaxel [12]. Front-line and second-line phase 3 studies comparing cabazitaxel 25 mg/m2, 20 mg/m2 cabazitaxel, and docetaxel 75 mg/m2, all delivered on an every 3-week interval, have recently been reported to demonstrate similar survival outcomes [13], [14]. Mitoxantrone is an anthracenedione approved for use in mCRPC on the basis of pain palliation, which has also demonstrated significant antitumor activity including prostate-specific antigen (PSA) and objective tumor responses in prior clinical studies [15], [16]. Given the largely nonoverlapping mechanisms of action and toxicity profile of these 2 agents, aside from potential additive myelosuppression that may be managed with prophylactic use of growth factors, and demonstrating single-agent activity with both agents, additional antitumor activity may be achieved with combination therapy with an acceptable safety profile.
Consequently, a multicenter phase 1 trial was conducted through the Prostate Cancer Clinical Trials Consortium to determine the maximally tolerated dose (MTD) and recommended phase 2 dose of cabazitaxel, mitoxantrone, and prednisone in patients with chemotherapy-naïve mCRPC.
Section snippets
Study population
Eligible patients had histologically confirmed prostate adenocarcinoma with evidence of progressive, metastatic, castration-resistant disease by PCWG2 criteria and a minimum serum PSA level of 2 ng/ml [17]. An Eastern Cooperative Oncology Group performance status of 0 to 2 was required, as was adequate hematologic, renal, and hepatic function. Patients were required to have a castrate level of testosterone (<50 ng/dl). Cardiac ejection fraction was required to be greater than institutional lower
Baseline characteristics and patient disposition
A total of 25 patients were enrolled between June 2012 and February 2016. Baseline characteristics of the patients are shown in Table 1. Characteristics were largely representative of a first-line chemotherapy population in mCRPC, with approximately 25% of patients with visceral metastases and 33% of patients with requirement for opioid analgesics for cancer-associated pain. Most patients (72%) had received abiraterone before enrollment. In contrast, owing to the timelines in which the study
Discussion
In the current phase 1 study, the approved single-agent dose of mitoxantrone (12 mg/m2) administered in combination with cabazitaxel 20 mg/m2, both delivered on day 1 of an every 21-day cycle, was established as the maximally tolerated and recommended phase 2 dose, in conjunction with daily prednisone and primary prophylactic growth factor support. The treatment combination produced objective and PSA responses in 71% and 60% of patients, respectively, and responses were durable in most patients.
Acknowledgments
This work was supported by Sanofi-Aventis. The funding source was not involved with study design, data analysis and interpretation, or preparation of the manuscript.
References (24)
- et al.
Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised phase 3 trial
Lancet Oncol
(2013) - et al.
Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial
Lancet Oncol
(2013) - et al.
Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial
Lancet Oncol
(2013) - et al.
Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial
Lancet
(2010) - et al.
Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance?
Ann Oncol
(2012) - et al.
Integrative genomics of advanced prostate cancer
Cell
(2015) - et al.
Cancer incidence and mortality worldwide: sources, methods, and major patterns in GLOBOCAN 2012
Int J Cancer
(2015) - et al.
Chemohormonal therapy in metastatic hormone-sensitive prostate cancer
New Engl J Med
(2015) - et al.
Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer
New Engl J Med
(2004) - et al.
Randomized, double-blind, placebo-controlled phase 3 trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401
J Clin Oncol
(2012)
Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer
J Clin Oncol
Phase III, randomized, placebo-controlled study of docetaxel in combination with zibotentan in patients with metastatic castration-resistant prostate cancer
J Clin Oncol
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