Dataset Information

End points and outcomes in castration-resistant prostate cancer: from clinical trials to clinical practice.

ABSTRACT: New therapeutic approaches for castration-resistant prostate cancer (CRPC) introduce new treatment dilemmas: how best to sequence these options to maximally benefit patients, what tests to perform before and after treatment to assess disease status, and how to interpret the test results and use them to guide treatment. New and specific end points for different classes of drugs are needed to provide the information to guide these treatment decisions. In 2008, the Prostate Cancer Working Group 2 consensus criteria for early-phase clinical trials redefined clinical trial end points as first, to control, relieve, or eliminate disease manifestations present when treatment is started and second, to prevent or delay future disease manifestations. Disease manifestations include prostate-specific antigen (PSA), soft-tissue disease (nodes and/or viscera), bone disease (most common site of spread), and symptoms. Recent US Food and Drug Administration (FDA) approvals for CRPC therapies have been based on the prevent/delay end points that reflect unequivocal benefit to a patient: prolongation of life or reduction in skeletal-related events (SREs). For the practicing oncologist, the control/relieve/eliminate outcomes should serve primarily to inform the decision of whether to continue therapy. In this review, we consider individual end points such as PSA, imaging, and patient-reported outcomes in the context of the control/relieve/eliminate and prevent/delay framework. We address the time-to-event end points of metastasis prevention, SRE, time to progression, and overall survival in the context of regulatory approvals. We also discuss circulating tumor cells measured with the CellSearch assay, recently cleared by the FDA for monitoring CRPC.

SUBMITTER: Scher HI

PROVIDER: S-EPMC3675708 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

End points and outcomes in castration-resistant prostate cancer: from clinical trials to clinical practice.

Scher Howard I HI Morris Michael J MJ Basch Ethan E Heller Glenn G

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20110822 27

New therapeutic approaches for castration-resistant prostate cancer (CRPC) introduce new treatment dilemmas: how best to sequence these options to maximally benefit patients, what tests to perform before and after treatment to assess disease status, and how to interpret the test results and use them to guide treatment. New and specific end points for different classes of drugs are needed to provide the information to guide these treatment decisions. In 2008, the Prostate Cancer Working Group 2 c ...[more]

PMID: 21859988

Similar Datasets

Project description:PurposeEvolving treatments, disease phenotypes, and biology, together with a changing drug development environment, have created the need to revise castration-resistant prostate cancer (CRPC) clinical trial recommendations to succeed those from prior Prostate Cancer Clinical Trials Working Groups.MethodsAn international expert committee of prostate cancer clinical investigators (the Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) was reconvened and expanded and met in 2012-2015 to formulate updated criteria on the basis of emerging trial data and validation studies of the Prostate Cancer Clinical Trials Working Group 2 recommendations.ResultsPCWG3 recommends that baseline patient assessment include tumor histology, detailed records of prior systemic treatments and responses, and a detailed reporting of disease subtypes based on an anatomic pattern of metastatic spread. New recommendations for trial outcome measures include the time to event end point of symptomatic skeletal events, as well as time to first metastasis and time to progression for trials in the nonmetastatic CRPC state. PCWG3 introduces the concept of no longer clinically benefiting to underscore the distinction between first evidence of progression and the clinical need to terminate or change treatment, and the importance of documenting progression in existing lesions as distinct from the development of new lesions. Serial biologic profiling using tumor samples from biopsies, blood-based diagnostics, and/or imaging is also recommended to gain insight into mechanisms of resistance and to identify predictive biomarkers of sensitivity for use in prospective trials.ConclusionPCWG3 moves drug development closer to unmet needs in clinical practice by focusing on disease manifestations most likely to affect prognosis adversely for therapeutics tested in both nonmetastatic and metastatic CRPC populations. Consultation with regulatory authorities is recommended if a trial is intended to seek support for drug approval.

Project description:Background: Enzalutamide is useful for the treatment of castration-resistant prostate cancer (CRPC). Despite its usefulness, adverse events (AEs) sometimes force patients to discontinue treatment. To maximize patient care, we developed an ambulatory care pharmacy practice that allows collaboration between a pharmacist and urologist to manage patients with CRPC receiving enzalutamide. In this study, we investigated the efficacy of this collaborative management. Methods: A retrospective chart review of 103 patients with CRPC receiving enzalutamide in our hospital between May 2014 and December 2020 was performed. Our collaborative management was implemented in October 2016. Before being examined by urologists, patients visited the oncology pharmacy consultation room for a face-to-face consultation, wherein the oncology pharmacists assessed factors such as adherence to enzalutamide, any AEs and their grades, and provided their suggestions to the urologists. The time to enzalutamide discontinuation and prostate-specific antigen progression were compared between patients who started enzalutamide before (n = 41) and after (n = 62) the implementation of the collaborative management. A multivariate Cox regression analysis was performed to analyze the factors associated with enzalutamide discontinuation. Results: After implementing collaborative management, the pharmacists had 881 patient consultations. Among the 476 suggestions from pharmacists, 345 were accepted by urologists. The most frequent suggestion was supportive care in enzalutamide treatment (224 suggestions). Multivariate analysis showed that collaborative management [hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.31-0.89, p = 0.017] and higher prostate-specific antigen (PSA; HR 2.41, 95% CI 1.36-4.28, p = 0.003) were significantly associated with enzalutamide discontinuation. The median time to discontinuation (18.9 vs. 7.6 months, p = 0.012), time to discontinuation due to AEs (not reached in both groups, p = 0.001), and time to PSA progression (13.3 vs. 5.8 months, p = 0.002) were all significantly longer in the after group. Conclusions: We implemented a pharmacist-urologist collaborative management program for outpatients with CRPC receiving enzalutamide. The results revealed that collaborative management was useful for prolonging the time to enzalutamide discontinuation.

Project description:BackgroundBoth changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC.MethodsWe performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models.ResultsThe 3LS was associated with shorter OS in the discovery (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies.ConclusionsElevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.

Project description:PurposeTo provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC).MethodsThe American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature.ResultsWhen added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib.RecommendationsContinue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or combinations of therapies. Palliative care should be offered to all patients.

Dataset Information

End points and outcomes in castration-resistant prostate cancer: from clinical trials to clinical practice.

Publications

End points and outcomes in castration-resistant prostate cancer: from clinical trials to clinical practice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets