A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients

Spreafico, Anna; N., Kim; Sridhar, Srikala S.; Smith, David C.; Carducci, Michael A.; Kavsak, Peter A.; Wong, Tracy; Wang, Lisa; Ivy, S. Percy; Mukherjee, Som D.; Kollmannsberger, Christian; Sukhai, Mahadeo A.; Takebe, Naoko; Kamel‐Reid, Suzanne; Siu, Lillian L.; Hotte, Sébastien J.

doi:10.1007/s10637-014-0106-5

Cited by 31 publications

(18 citation statements)

References 78 publications

(66 reference statements)

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“…All patients received initial androgen deprivation therapy or combined androgen blockade treatment and were refractory to each treatment. The definition of CRPC was set by the Prostate Cancer Working Group 2 [17]. The patients who received both ABI and ENZ were classified as the first-line treatment group.…”

Section: Patientsmentioning

confidence: 99%

A high neutrophil-to-lymphocyte ratio is a poor prognostic factor for castration-resistant prostate cancer patients who undergo abiraterone acetate or enzalutamide treatment

et al. 2020

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Background Inflammatory cytokine markers, including the neutrophil-to-lymphocyte ratio (NLR), monocyte-lymphocyte ratio, and platelet-to-lymphocyte ratio, play important roles as prognostic markers in several solid malignancies, including prostate cancer. We previously reported the NLR as a poor prognostic marker in bladder cancer, upper-urothelial carcinoma, adrenocortical carcinoma, penile cancer, and prostate cancer. This study examined the importance of the NLR as a prognostic marker for castration-resistant prostate cancer (CRPC) patients who received abiraterone acetate or enzalutamide. Methods A total of 805 prostate cancer patients developed in CRPC status were enrolled in this study. Of these patients, 449 received abiraterone acetate (ABI; 188 cases) or enzalutamide (ENZ; 261 cases) treatment, and the pre-treatment NLR values of these patients were obtained. We investigated the prognosis in those with higher and lower NLR values. Results The median NLR was 2.90, and a receiver operating characteristics analysis suggested a candidate cut-off point of 3.02. The median overall survival (OS) was 17.3 months in the higher NLR group (≥3.02) and 27.3 months in the lower NLR group (< 3.02) (p < 0.0001). This trend was also observed in both the ABI and ENZ groups (ABI: 29.3 vs. 15.1 months; ENZ: NR vs. 19.5 months; p < 0.0001 and < 0.0001, respectively). A multivariate analysis revealed that a higher NLR was an independent risk factor. The NLR value was thus shown to be correlated with the prostate cancer progression. Conclusions A higher NLR was associated with a poorer OS for CRPC patients who received ABI or ENZ. The NLR was positively correlated with prostate cancer progression.

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Section: Patientsmentioning

confidence: 99%

A high neutrophil-to-lymphocyte ratio is a poor prognostic factor for castration-resistant prostate cancer patients who undergo abiraterone acetate or enzalutamide treatment

et al. 2020

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“…The institutional review board of Yokohama City University Medical Center was approved this study (D1603004). The de nition of CRPC was set by the Prostate Cancer Working Group 2 [9]. Patients' background characteristics, including the initial prostate-speci c antigen (PSA) level, initial metastatic status, Gleason score, observation period, time to CRPC, pre-chemotherapy, age at baseline, PSA at baseline, ALP at baseline, LDH as baseline, and initial ABI/ENZ treatment, are shown in Table 1.…”

Section: Patientsmentioning

confidence: 99%

The Development and Validation of a Prognostic Nomogram and Nomogram Application Software Among Men Treated with Abiraterone Acetate and/or Enzalutamide for Metastatic Castration-resistant Prostate Cancer

Kawahara

Saigusa

Yoneyama

et al. 2020

Preprint

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Background:With widespread medication choices for metastatic castration-resistant prostate cancer (mCRPC) is now available, on the other hand biomarker to predict the efficacy of each mCRPC treatment has not been established.Objective:This study developed prognostic nomogram to predict prognosis in CRPC patients who received abiraterone acetate (ABI) and/or enzalutamide (ENZ).Design, Setting, and Participants:A total of 568 mCRPC patients received ABI and/or ENZ from 2012 to 2017 were enrolled in this study. We developed prognostic nomogram based on the risk factors by Cox proportional hazards regression model.Outcome Measurements and Statistical Analysis:The nomogram was also assessed for discriminatory ability with the concordance index (C-index). We repeated 5-fold cross-validation 2000 times to estimate the C-index and reported the means of the estimated C-index for the training and validation sets. And we also developed nomogram application software (app) based on this nomogram.Results and Limitations:The median overall survival (OS) was 24.7 months. A multivariable analysis showed that the time to CRPC, pre-chemotherapy, baseline PSA, baseline ALP, and baseline LDH were independent risk factors for the OS (HR: 0.521, 1.681, 1.439, 1.827, 12,123, p:0.001, 0.001, <0.001, 0.019, <0.001)). C-index was 0.72 in training cohort and 0.71 in validation cohort.Conclusion:We developed nomograms to predict the OS for Japanese mCRPC patients who received ABI and/or ENZ. The advent of mCRPC prognosis prediction app will facilitate greater accessibility for clinical use.Patient SummaryThis study developed and validated a nomogram for predicting the prognosis of mCRPC patients who receive ABI/ENZ treatment using clinical information. This study also developed mobile app to facilitate clinical usage.

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“…Together, these observations suggest that dasatinib might be an effective treatment for patients with prostate tumours expressing low levels of AR signalling. The antitumour activity of dasatinib has been assessed in several phase II clinical trials of patients with mCRPC, showing promising results (in terms of objective response and disease control rates 95,96 ), as well as in phase II 97 and phase III 98 randomized clinical trials. These controlled trials, however, did not meet their objectives of improved progression-free survival (PFS) and overall survival, potentially because patients were not stratified according to AR activity.…”

Section: Treatment-induced Prostate Lineagesmentioning

confidence: 99%

Strategies to avoid treatment-induced lineage crisis in advanced prostate cancer

Roubaud

Liaw

et al. 2016

Nat Rev Clin Oncol

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The increasing potency of therapies that target the androgen receptor (AR) signalling axis has correlated with a rise in the proportion of patients with prostate cancer harbouring an adaptive phenotype, termed treatment-induced lineage crisis. This phenotype is characterized by features that include soft-tissue metastasis and/or resistance to standard anticancer therapies. Potent anticancer treatments might force cancer cells to evolve and develop alternative cell lineages that are resistant to primary therapies, a mechanism similar to the generation of multidrug-resistant microorganisms after continued antibiotic use. Herein, we assess the hypothesis that treatmentadapted phenotypes harbour reduced AR expression and/or activity, and acquire compensatory strategies for cell survival. We highlight the striking similarities between castration-resistant prostate cancer and triple-negative breast cancer, another poorly differentiated endocrine malignancy. Alternative treatment paradigms are needed to avoid therapy-induced resistance. Herein, we present a new clinical trial strategy designed to evaluate the potential of rapid drug cycling as an approach to delay the onset of resistance and treatment-induced lineage crisis in patients with metastatic castration-resistant prostate cancer.Potent clinical suppression of androgen receptor (AR) signalling has been achieved with the pharmacological inhibitors abiraterone acetate 1,2 and enzalutamide 3,4 (drugs that were approved by the FDA in 2011 and 2014, respectively), resulting in significant survival benefits for men with metastatic castration-resistant prostate cancer (mCRPC). Emerging evidence suggests, however, that the prolonged therapeutic use of abiraterone and enzalutamide induces adaptive clinical phenotypes -including histological dedifferentiation and lineage alterations, such as treatment-induced neuroendocrine prostate cancer (t-NEPC) 5 and treatment-induced epithelial-to-mesenchymal transition 6,7 (t-EMT) (BOX 1). Such resistant phenotypes, in turn, might cause aggressive visceral metastases, a trend that has been reported with increasing prevalence in patients with prostate cancer who have received long-term androgen deprivation therapy (ADT) 5,[8][9][10][11][12] . While the mechanisms Correspondence to D.J.M. david.mulholland@mssm.edu. Author contributions: G.R. and D.J.M researched data and wrote the manuscript. All authors discussed the article's contents, revised and edited the manuscript before submission. B.C.L. and W.K.O. designed the PRINT clinical protocol. Competing interests statement:The authors declare no competing interests. Increased research emphasis should be placed on the development of preclinical models, in which the effects of treatment-induced resistance can be tested directly, as well as on the development of alternative treatment strategies that could be used to prolong the survival of men with advanced-stage prostate cancer by delaying the onset of resistance and minimizing toxicities. We suggest a new treatment approach, ...

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A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients

Cited by 31 publications

References 78 publications

A high neutrophil-to-lymphocyte ratio is a poor prognostic factor for castration-resistant prostate cancer patients who undergo abiraterone acetate or enzalutamide treatment

A high neutrophil-to-lymphocyte ratio is a poor prognostic factor for castration-resistant prostate cancer patients who undergo abiraterone acetate or enzalutamide treatment

The Development and Validation of a Prognostic Nomogram and Nomogram Application Software Among Men Treated with Abiraterone Acetate and/or Enzalutamide for Metastatic Castration-resistant Prostate Cancer

Strategies to avoid treatment-induced lineage crisis in advanced prostate cancer

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