TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial

Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, UK.
The Lancet (Impact Factor: 45.22). 10/2010; 376(9747):1147-54. DOI: 10.1016/S0140-6736(10)61389-X
Source: PubMed


Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment.
We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were randomly assigned to receive either 12 mg/m(2) mitoxantrone intravenously over 15-30 min or 25 mg/m(2) cabazitaxel intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. Analysis was by intention to treat. This study is registered at, NCT00417079.
755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the intention-to-treat analysis. At the cutoff for the final analysis (Sept 25, 2009), median survival was 15·1 months (95% CI 14·1-16·3) in the cabazitaxel group and 12·7 months (11·6-13·7) in the mitoxantrone group. The hazard ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0·70 (95% CI 0·59-0·83, p<0·0001). Median progression-free survival was 2·8 months (95% CI 2·4-3·0) in the cabazitaxel group and 1·4 months (1·4-1·7) in the mitoxantrone group (HR 0·74, 0·64-0·86, p<0·0001). The most common clinically significant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303 [82%] patients vs mitoxantrone, 215 [58%]) and diarrhoea (23 [6%] vs one [<1%]). 28 (8%) patients in the cabazitaxel group and five (1%) in the mitoxantrone group had febrile neutropenia.
Treatment with cabazitaxel plus prednisone has important clinical antitumour activity, improving overall survival in patients with metastatic castration-resistant prostate cancer whose disease has progressed during or after docetaxel-based therapy.

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Available from: Mustafa ÖZGÜROĞLU, Mar 18, 2014
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    • "The drivers of prostate cancer cell proliferation, metastasis, and evasion of apoptosis include activation of the androgen receptor, carcinogenic signaling within cells, and the effect of survival signals from the microenvironment. Regression or stabilization of cancer burden occurs in some CRPC patients through the use of hormonal therapy [2] [3], cytotoxic therapy [4] [5], and immune-based therapy [6] that abrogates one or more of these drivers. An alpha-emitting radiopharmaceutical [7] is also currently used clinically in CRPC patients with skeletal metastases to prolong overall survival and localized radiation cell killing in bone metastases. "
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    ABSTRACT: Preclinical xenograft models have contributed to advancing our understanding of the molecular basis of prostate cancer and to the development of targeted therapy. However, traditional preclinical in vivo techniques using caliper measurements and survival analysis evaluate the macroscopic tumor behavior, whereas tissue sampling disrupts the microenvironment and cannot be used for longitudinal studies in the same animal. Herein, we present an in vivo study of [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) designed to evaluate the metabolism within the microenvironment of LAPC4-CR, a unique murine model of castration-resistant prostate cancer. Mice bearing LAPC4-CR subcutaneous tumors were administered [(18)F]-FDG via intravenous injection. After a 60-minute distribution phase, the mice were imaged on a PET/CT scanner with submillimeter resolution; and the fused PET/CT images were analyzed to evaluate tumor size, location, and metabolism across the cohort of mice. The xenograft tumors showed [(18)F]-FDG uptake that was independent of tumor size and was significantly greater than uptake in skeletal muscle and liver in mice (Wilcoxon signed-rank P values of .0002 and .0002, respectively). [(18)F]-FDG metabolism of the LAPC4-CR tumors was 2.1 ± 0.8 ID/cm(3)*wt, with tumor to muscle ratio of 7.4 ± 4.7 and tumor to liver background ratio of 6.7 ± 2.3. Noninvasive molecular imaging techniques such as PET/CT can be used to probe the microenvironment of tumors in vivo. This study showed that [(18)F]-FDG-PET/CT could be used to image and assess glucose metabolism of LAPC4-CR xenografts in vivo. Further work can investigate the use of PET/CT to quantify the metabolic response of LAPC4-CR to novel agents and combination therapies using soft tissue and possibly bone compartment xenograft models. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Translational oncology
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    • "Docetaxel became the reference first-line treatment for metastatic castration-resistant prostate cancer (mCRPC) in 2004 [1], but it has only recently been demonstrated that new agents (NAs) such as cabazitaxel (CAB), abiraterone acetate (AA), and enzalutamide (ENZ) are active in mCRPC patients who have received first-line docetaxel [2] [3] [4]. "
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    ABSTRACT: The availability of new agents (NAs) active in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel treatment (abiraterone acetate, cabazitaxel, and enzalutamide) has led to the possibility of using them sequentially to obtain a cumulative survival benefit. To provide clinical outcome data relating to a large cohort of mCRPC patients who received a third-line NA after the failure of docetaxel and another NA. We retrospectively reviewed the clinical records of patients who had received at least two successive NAs after the failure of docetaxel. The independent prognostic value of a series of pretreatment covariates on the primary outcome measure of overall survival was assessed using Cox regression analysis. We assessed 260 patients who received one third-line NA between January 2012 and December 2013, including 38 who received a further NA as fourth-line therapy. The median progression-free and overall survival from the start of third-line therapy was, respectively, 4 mo and 11 mo, with no significant differences between the NAs. Performance status, and haemoglobin and alkaline phosphatase levels were the only independent prognostic factors. The limitations of the study are mainly due its retrospective nature and the small number of patients treated with some of the sequences. We were unable to demonstrate a difference in the clinical outcomes of third-line NAs regardless of previous NA therapy. It is debated which sequence of treatments to adopt after docetaxel. Our data do not support the superiority of any of the three new agents in third-line treatment, regardless of the previously administered new agent. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
    Full-text · Article · Oct 2014 · European Urology
    • "A high proportion of patients experience significant toxicity; 42% nausea, vomiting or both, 30% sensory neuropathy and 26% more than or equal to one serious adverse event (Petrylak et al, 2004; Tannock et al, 2004). The newer second-line cytotoxic, Cabazitaxel, similarly improves survival, but remains toxic and benefits o50% of patients (de Bono et al, 2010). Clearly, patients would benefit from knowing early in the treatment schedule, who will benefit from chemotherapy to avoid the morbidity in an elderly population. "
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    ABSTRACT: Background: Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). Methods: Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. Results: The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). Conclusions: We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.
    No preview · Article · Aug 2014 · British Journal of Cancer
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