Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1–2 trial

Corn, Paul G.; Heath, Elisabeth I.; Zurita, Amado J.; Ramesh, Naveen; Xiao, Lianchun; Sei, Emi; Li-Ning-Tapia, Elsa M.; Tu, Shi Ming; Subudhi, Sumit K.; Wang, Jennifer; Wang, Xuemei; Efstathiou, Eleni; Thompson, Timothy C.; Troncoso, Patricia; Navin, Nicholas E.; Logothetis, Christopher J.; Aparicio, Ana

doi:10.1016/s1470-2045(19)30408-5

Cited by 131 publications

(131 citation statements)

References 24 publications

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“…A phase I/II trial recently demonstrated that men with AVPC have a better Progression free survival after cabazitaxel + carboplatin treatment as compared to cabazitaxel alone [22]. In agreement, our in vivo preclinical results validate these data suggesting that therapeutic response to cisplatin-based chemotherapy in docetaxel-resistant mCRPC patients might be predicted by the level of CXCR2/BCL-2 expression before treatment with this platinum.…”

Section: Discussionsupporting

confidence: 86%

“…Based on our results indicating that docetaxel triggers a marked reduction in the CXCR2/BCL-2 axis, and the clinical benefit observed for the combination of platinums and taxanes in mCRPC [22] , we hypothesized that the docetaxel-resistant PC cells sensitivity to platinum treatment is CXCR2-dependent ( Figure 3). As predicted, docetaxel-resistant DU145-DR and PC3-DR cells were significantly more sensitive to cisplatin and carboplatin that their respective parental cells (DU145-DR, p = 0.004 and <0.0001; PC3-DR p < 0.0001 and < 0.0001 for cisplatin and carboplatin, respectively) ( Figure 3A, B).…”

Section: Cxcr2 Downregulation Sensitizes Pc Cells To Platinummentioning

confidence: 99%

“…To our knowledge, at least two independent randomized phase 1 and phase 1-2 clinical trials [10,22] have assessed the efficacy of taxane-planinum combinations in men with mCRPC with apparently contradictory results. To provide preclinical evidence and to test the hypothesis that platinum added to taxane may improve survival and response in aggressive mCRPC, we conducted similar trials in NPK PC GEMM ( Figure 4A).…”

Section: Taxane Treatment Sensitizes a Mouse Crpc Model To Cisplatin mentioning

confidence: 99%

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Taxane induces attenuation of the CXCR2/BCL-2 axis and sensitize prostate cancer to platinum-based treatments

Porras

Wang

Palomero

et al. 2020

Preprint

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BackgroundTaxanes are the most active chemotherapy agents in metastatic castration resistant prostate cancer (mCRPC) patients, yet resistance almost invariably occurs representing an important clinical challenge. Taxane-platinum combinations have shown clinical benefit in a subset of patients but the mechanistic basis and biomarkers remain elusive.ObjectiveTo identify mechanisms and response biomarkers for the antitumor efficacy of taxane-platinum combinations in mCRPC.Design, setting, and participantsTranscriptomic data from a publicly available mCRPC dataset of taxane-exposed and naïve patients was analysed to identify response biomarkers and emerging vulnerabilities. Functional and preclinical validation was performed in taxane resistant mCRPC cell lines and genetically engineered mouse models (GEMM).InterventionmCRPC cells were treated with docetaxel, cisplatin, carboplatin and the CXCR2 inhibitor, SB265610. Gain and loss of function in culture of CXCR2 was achieved by overexpression or siRNA-silencing. Preclinical assays in GEMM mice tested the anti-tumor efficacy of taxane-platinum combinations.Outcome measurements and statistical analysisProliferation, apoptosis and colony assays measured drug activity in vitro. Preclinical endpoints in mice included growth, survival and histopathology. Changes in CXCR2, BCL-2 and chemokines were analysed by RT-qPCR and Western Blot. Human expression data was analyzed using GSEA, hierarchical clustering and correlation studies. GraphPad Prism software, R-studio, were used for statistical and data analyses.Results and limitationsTranscriptomic data from taxane-exposed human mCRPC tumors correlates with a marked negative enrichment of apoptosis and inflammatory response pathways accompanied by a marked downregulation of CXCR2 and BCL-2. Mechanistically, we show that docetaxel treatment inhibits CXCR2 and that BCL-2 downregulation occurs as a downstream effect. Further, we demonstrated that taxane resistance is directly associated to CXCR2 expression and that targeting of CXCR2 sensitizes prostate cancer (PC) cells to cisplatin. Finally, taxane-platinum combinations in vivo are highly synergistic and previous exposure to taxanes sensitizes mCRPC tumors to second line cisplatin treatment.ConclusionsTogether our data identifies an acquired vulnerability in taxane treated mCRPC patients with potential predictive activity for platinum-based treatments.Patient summaryA subset of patients with aggressive and therapy resistant PC benefits from taxane-platinum combination chemotherapy however, we lack biomarkers and mechanistic basis about how that synergistic effect occurs. Here, using patient data and preclinical models, we found that taxanes reduce cancer cell scape mechanisms to chemotherapy-induced cell death, hence turning these cells more vulnerable to additional platinum treatment.

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Section: Discussionsupporting

confidence: 86%

Section: Cxcr2 Downregulation Sensitizes Pc Cells To Platinummentioning

confidence: 99%

Section: Taxane Treatment Sensitizes a Mouse Crpc Model To Cisplatin mentioning

confidence: 99%

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Taxane induces attenuation of the CXCR2/BCL-2 axis and sensitize prostate cancer to platinum-based treatments

Porras

Wang

Palomero

et al. 2020

Preprint

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“…However, a subgroup of patients seemed to derive benefit, 3 namely patients with aggressive variant adenocarcinoma of the prostate (with alterations in at least 2 of the following: TP53 [OMIM 191170 ], RB1 [OMIM 614041 ], and PTEN , detected by next-generation sequencing or immunohistochemistry). 27 With emerging data of a meaningful prevalence of somatic and germline DNA repair gene aberrations in patients with advanced prostate cancer 28 and activity of PARP inhibitors in these patients, 12 interest in platinum-based treatment arose again, with the hypothesis of increased activity in this specific subpopulation of patients with prostate cancer, analogous to data from patients with TNBC. Generally, combination treatment should be recommended; however, monotherapy remains an option, and there is expert consensus from the 2019 advanced prostate cancer consensus conference for carboplatin with target area under the curve (AUC) of 5 to 6 every 3 weeks as a preferred regimen.…”

Section: Discussionmentioning

confidence: 99%

Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations

et al. 2020

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Key Points Question Is there a role for platinum-based treatment in molecularly selected patients with advanced prostate cancer? Findings In a case series of 508 patients, platinum-based therapy was associated with antitumor activity, especially among patients with known DNA repair gene aberrations. In patients with DNA repair gene aberrations, nearly half had a decrease in prostate-specific antigen levels of at least 50% and experienced soft tissue responses. Meaning In patients with prostate cancer and DNA repair gene aberrations, platinum-based therapy may be considered a treatment option.

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“…More recently, a phase I-II RCT has shown promising activity with carboplatin added to CAB in metastatic castrationresistant prostate cancers. 24 Although the results require further confirmation, these findings may support decision-making in patients with mCRPC and aggressive disease. Different non-randomized, retrospective studies have demonstrated platinum-based chemotherapies to be active in men with neuroendocrine prostate cancer.…”

Section: Recommendation 4 In Patients With Mcrpc Who Have Progressedmentioning

confidence: 84%

Expert recommendations on the management of patients with metastatic castration-resistant prostate cancer who progress after CHAARTED or LATITUDE

et al. 2020

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Objective: Our aim was to provide practical recommendations on the management of patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel plus androgen-deprivation therapy (ADT) or abiraterone plus ADT. Methods: Systematic literature review (SLR), nominal group meeting, and Delphi process. A panel of 12 experts was established who defined the scope, users, and sections of the document. We performed an SLR in order to assess the efficacy and safety of available drugs in patients with mCRPC. Abstracts from the American Society of Oncology and European Society for Medical Oncology meetings were also examined. The results were discussed during an expert meeting in which 14 recommendations were generated. The level of agreement with the recommendations was also tested by 13 additional experts following the Delphi process. Recommendations were voted by means of scores ranging from 0 (total disagreement) to 10 (total agreement). We defined agreement when at least 70% of the experts voted ⩾7. Next, we assigned a level of evidence and grade to the recommendation using the Oxford Centre for Evidence-based Medicine Levels of Evidence, following which the final document was drafted. Results: The literature search did not find any articles meeting the inclusion criteria. Finally, 13 out of 14 recommendations were accepted after two Delphi rounds (two were modified after the first round). They pertain to general and individual case-based treatment recommendations. Conclusions: In mCRPC patients who have progressed after docetaxel or abiraterone plus ADT in the metastatic hormone-sensitive prostate cancer setting, these recommendations may support treatment decision-making, due to the lack of evidence or other globally accepted sequencing algorithms.

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Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1–2 trial

Cited by 131 publications

References 24 publications

Taxane induces attenuation of the CXCR2/BCL-2 axis and sensitize prostate cancer to platinum-based treatments

Taxane induces attenuation of the CXCR2/BCL-2 axis and sensitize prostate cancer to platinum-based treatments

Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations

Expert recommendations on the management of patients with metastatic castration-resistant prostate cancer who progress after CHAARTED or LATITUDE

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