Weekly cabazitaxel plus prednisone is effective and less toxic for ‘unfit’ metastatic castration-resistant prostate cancer: Phase II Spanish Oncology Genitourinary Group (SOGUG) trial

Climent, Miguel Ángel; Pérez-Valderrama, Begoña; Mellado, Begoña; Parra, E.M. Fernandez; Calvo, Ovidio Fernández; Olza, María Ochoa de; Romay, Laura Muinelo; Anido, Urbano; Domènech, Montserrat; Polo, Susana Hernando; Arija, José Ángel Arranz; Caballero, Cristina; Fita, María José Juan; Castellano, Daniel

doi:10.1016/j.ejca.2017.09.028

Cited by 19 publications

(11 citation statements)

References 30 publications

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“…Climent et al have assessed baseline CTC numbers in 56 patients receiving cabazitaxel therapy. They also found an association between CTC count and PFS, however they did not find a statistically significant association between CTC count and OS [12].…”

Section: Discussionmentioning

confidence: 99%

“…In prostate cancer, the enumeration of CTCs is a strong independent prognostic factor for progression-free survival (PFS) and overall survival (OS) both before and during therapy, as shown in multiple studies [8,9,10,11]. However, the prognostic value for patients treated with cabazitaxel has only been analyzed in a small series of 56 patients [12].…”

Section: Introductionmentioning

confidence: 99%

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Circulating Tumor Cell Enumeration and Characterization in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Cabazitaxel

Kruijff

Sieuwerts

Onstenk

et al. 2019

Cancers

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(1) Background: Markers identifying which patients with metastatic, castration-resistant prostate cancer (mCRPC) will benefit from cabazitaxel therapy are currently lacking. Therefore, the aim of this study was to identify markers associated with outcome to cabazitaxel therapy based on counts and gene expression profiles of circulating tumor cells (CTCs). (2) Methods: From 120 mCRPC patients, CellSearch enriched CTCs were obtained at baseline and after 6 weeks of cabazitaxel therapy. Furthermore, 91 genes associated with prostate cancer were measured in mRNA of these CTCs. (3) Results: In 114 mCRPC patients with an evaluable CTC count, the CTC count was independently associated with poor progression-free survival (PFS) and overall survival (OS) in multivariable analysis with other commonly used variables associated with outcome in mCRPC (age, prostate specific antigen (PSA), alkaline phosphatase, lactate dehydrogenase (LDH), albumin, hemoglobin), together with alkaline phosphatase and hemoglobin. A five-gene expression profile was generated to predict for outcome to cabazitaxel therapy. However, even though this signature was associated with OS in univariate analysis, this was not the case in the multivariate analysis for OS nor for PFS. (4) Conclusion: The established five-gene expression profile in CTCs was not independently associated with PFS nor OS. However, along with alkaline phosphatase and hemoglobin, CTC-count is independently associated with PFS and OS in mCRPC patients who are treated with cabazitaxel.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Circulating Tumor Cell Enumeration and Characterization in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Cabazitaxel

Kruijff

Sieuwerts

Onstenk

et al. 2019

Cancers

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“…Besides, several studies support the utility and safety of Cab as either a second-or third-line agent after Doc; i.e. : (a) The re-challenge with Cab chemotherapy was shown as working in CRPCa patients treated with > 10 cycles of Doc, with an acceptable risk of adverse effects burden [10][11][12]; (b) Cab at a higher initial dose demonstrated longer survival duration after treatment than a lower initial dose for Doc-resistant mCRPCa patients [13]; (c) Cab/prednisone administered weekly to unfit mCRPCa patients appeared to be as effective as classical standard 3-week scheme (TROPIC study) but with significantly lower toxicities and better tolerance [14]; and (d) the combination of Cab and abiraterone was found to have a manageable safety profile and showed antitumor activity in patients previously treated with Doc and abiraterone [15]. Furthermore, the promising therapeutic findings on Cab benefits (as mono-or combined therapies) in other types of cancers such as cisplatin-resistant germ cell tumor cells [16], breast cancer [17,18], sorafenib-resistant hepatocellular carcinomas [19], mCRPCa [20,21], cytarabine-resistant leukemia [22], glioblastoma [23] or gliomas [24] impel for more studies to understand Cab modes of action.…”

Section: Introductionmentioning

confidence: 94%

The Wnt non-canonical signaling modulates cabazitaxel sensitivity in prostate cancer cells

et al. 2020

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BackgroundDespite new drugs, metastatic prostate cancer remains fatal. Growing interest in the latest approved cabazitaxel taxane drug has markedly increased due to the survival benefits conferred when used at an earlier stage of the disease, its promising new therapeutic combination and formulation, and its differential toxicity. Still cabazitaxel's mechanisms of resistance are poorly characterized. The goal of this study was thus to generate a new model of acquired resistance against cabazitaxel in order to unravel cabazitaxel's resistance mechanisms. MethodsDu145 cells were cultured with increasing concentrations of cabazitaxel, docetaxel/ taxane control or placebo/age-matched control. Once resistance was reached, Epithelial-to-Mesenchymal Translation (EMT) was tested by cell morphology, cell migration, and E/M markers expression profile. Cell transcriptomics were determined by RNA sequencing; related pathways were identified using IPA, PANTHER or KEGG software. The Wnt pathway was analyzed by western blotting, pharmacological and knock-down studies. ResultsWhile age-matched Du145 cells were sensitive to both taxane drugs, docetaxel-resistant cells were only resistant to docetaxel and cabazitaxel-resistant cells showed a partial crossresistance to both drugs concomitant to EMT. Using RNA-sequencing, the Wnt non-canonical pathway was identified as exclusively activated in cabazitaxel resistant cells while the Wnt canonical pathway was restricted to docetaxel-resistant cells. Cabazitaxel-resistant cells showed a minimal crossover in the Wnt-pathway-related genes linked to docetaxel resistance validating our unique model of acquired resistance to cabazitaxel. Pharmacological and western blot studies confirmed these findings and suggest the implication of the Tyrosine kinase Ror2 receptor in cabazitaxel resistant cells. Variation in Ror2 expression

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“…Prior use of abiraterone does not seem to impact the response to cabazitaxel [66] . A phase II trial reported a 34.9% PSA response rate in a 10 mg/m 2 weekly treatment schedule and reported a lower toxicity, 14.2% neutropenia and 35.7% diarrhea [67] .…”

Section: Current Treatment Patterns For Crpcmentioning

confidence: 99%

Metastatic prostate cancer remains incurable, why?

Dong

Zieren

Xue

et al. 2019

Asian Journal of Urology

126

107

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Metastatic prostate cancer patients present in two ways—with already disseminated disease at the time of presentation or with disease recurrence after definitive local therapy. Androgen deprivation therapy is given as the most effective initial treatment to patients. However, after the initial response, almost all patients will eventually progress despite the low levels of testosterone. Disease at this stage is termed castration resistant prostate cancer (CRPC). Before 2010, the taxane docetaxel was the first and only life prolonging agent for metastatic CRPC (mCRPC). The last decade has witnessed robust progress in CRPC therapeutics development. Abiraterone, enzalutamide, apalutamide and sipuleucel-T have been evaluated as first- and second-line agents in mCRPC patients, while cabazitaxel was approved as a second-line treatment. Radium-223 dichloride was approved in symptomatic patients with bone metastases and no known visceral metastases pre- and post-docetaxel. However, despite significant advances, mCRPC remains a lethal disease. Both primary and acquired resistance have been observed in CRPC patients treated by these new agents. It could be solely cell intrinsic or it is possible that the clonal heterogeneity in treated tumors may result from the adaptive responses to the selective pressures within the tumor microenvironment. The aim of this review is to list current treatment agents of CRPC and summarize recent findings in therapeutic resistance mechanisms.

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Weekly cabazitaxel plus prednisone is effective and less toxic for ‘unfit’ metastatic castration-resistant prostate cancer: Phase II Spanish Oncology Genitourinary Group (SOGUG) trial

Cited by 19 publications

References 30 publications

Circulating Tumor Cell Enumeration and Characterization in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Cabazitaxel

Circulating Tumor Cell Enumeration and Characterization in Metastatic Castration-Resistant Prostate Cancer Patients Treated with Cabazitaxel

The Wnt non-canonical signaling modulates cabazitaxel sensitivity in prostate cancer cells

Metastatic prostate cancer remains incurable, why?

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