Treatment and resistance mechanisms in castration-resistant prostate cancer: new implications for clinical decision making?

Purpose Metastatic castration-resistant prostate cancer (CRPC) is the lethal form of the disease. Many groups have performed mutational or immunohistochemistry (IHC) testing in metastatic CRPC to identify treatment targets. However, the frequency with which mutational or IHC data have an impact on clinical decision making and the outcomes of molecularly guided therapy in CRPC are largely unknown. We report our institution’s experience with mutational and IHC testing in patients with metastatic CRPC and its impact on clinical decision making and patient outcomes. Methods Between 2012 and 2015, 59 patients with CRPC underwent metastatic tissue biopsies and were genotyped with a 37–cancer gene panel in a Clinical Laboratory Improvement Amendments–certified laboratory. PTEN expression by IHC testing was also measured in 35 of these samples. A retrospective chart review was performed to determine whether the genomic information was acted upon and the outcome of patients whose treatment was guided by molecular testing. Results Forty-six of 59 patients with CRPC (78.0%) had biopsies with adequate tumor for mutational testing. Thirty-one of 46 subjects (67.4%) had mutations identified by sequencing. Of the 35 patients with CRPC whose biopsies were evaluated for PTEN expression by IHC testing, 13 had PTEN loss. Two patients had treatment on the basis of molecular testing, and one of these subjects had greater tumor control with molecularly guided therapy than his immediate prior therapy. Conclusion Targeted sequencing and IHC can identify clinically informative molecular abnormalities in CRPC. Despite this, a small minority of patients in our series underwent therapies guided by mutational or IHC testing. Actionability of abnormalities identified in metastatic CRPC may be improved with access to clinical trials, insurance approval for unapproved uses of existing anticancer drugs, and larger gene sequencing panels that include more frequently mutated genes.

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Clinical Decision Making in Castration-resistant Prostate Cancer According to Baseline Prostate-specific Antigen: Are We Measuring Disease Burden or Disease Biology?

European Urology ◽

10.1016/j.eururo.2014.08.069 ◽

2015 ◽

Vol 67 (2) ◽

pp. 231-232 ◽

Cited By ~ 1

Author(s):

Benjamin A. Gartrell ◽

Matthew D. Galsky

Keyword(s):

Prostate Cancer ◽

Decision Making ◽

Prostate Specific Antigen ◽

Disease Burden ◽

Clinical Decision Making ◽

Specific Antigen ◽

Clinical Decision ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Disease Biology

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State-of-the-Art Management for the Patient with Castration-Resistant Prostate Cancer in 2012

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2012.32.174 ◽

2012 ◽

pp. 289-291 ◽

Cited By ~ 2

Author(s):

Oliver Sartor

Keyword(s):

Prostate Cancer ◽

Clinical Decision Making ◽

Clinical Decision ◽

Phase Iii ◽

Castration Resistant Prostate Cancer ◽

Optimal Sequence ◽

Molecular Stratification ◽

Castration Resistant ◽

Radium 223 ◽

Phase Iii Trials

Overview: Much progress has been made in metastatic castration-resistant prostate cancer (CRPC), and multiple new U.S. Food and Drug Administration (FDA)-approved survival-prolonging drugs are now available. In 2004, docetaxel/prednisone was the first therapy shown to prolong survival. In 2010 and 2011, sipuleucel-T, cabazitaxel/prednisone, and abiraterone/prednisone were FDA approved. Two new agents, radium-223 and MDV-3100, have recently reported large phase III trials prolonging overall survival and will be submitted for regulatory approval in 2012. One can now begin to ask, is there an optimal sequence for therapies in metastatic CRPC? Despite the recent progress, there is much we do not know and virtually no information on this important question. We know that abiraterone/prednisone and cabazitaxel/prednisone are appropriate choices for a patient after receiving docetaxel, but we do not know what, if anything, represents the optimal sequence for abiraterone and cabazitaxel. In fact we do not understand how one therapy may affect the response to a subsequent therapy. We are also aware that the pre- and postdocetaxel spaces represent regulatory rather than biologic divisions. In addition, despite the proven role of docetaxel/prednisone, many patients with CRPC are not considered to be suitable for chemotherapy, and worldwide many never receive any form of chemotherapy. What is the optimal management for these patients? Taken together it is reasonable to assess patient preferences, prior therapies and response/tolerance to prior therapies, burden of disease, comorbidities, current symptoms, drug toxicities, out-of-pocket costs, etc., in clinical decision making. Given the many factors we do not know, it is hard to be dogmatic in approaching the therapeutic options for the patient with CRPC. We will likely soon move beyond the current sequencing paradigm and begin to assess new combinations in a systematic and rational fashion. Perhaps one day, in the not too distant future, we will develop molecular “stratification systems” to better guide therapeutic choices in CRPC.

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Clinical Utility of CLIA-Grade AR-V7 Testing in Patients With Metastatic Castration-Resistant Prostate Cancer

JCO Precision Oncology ◽

10.1200/po.17.00127 ◽

2017 ◽

pp. 1-9 ◽

Cited By ~ 13

Author(s):

Mark C. Markowski ◽

John L. Silberstein ◽

James R. Eshleman ◽

Mario A. Eisenberger ◽

Jun Luo ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Messenger Rna ◽

Clinical Decision Making ◽

Clinical Laboratory ◽

Specific Antigen ◽

Clinical Decision ◽

The United States ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

Purpose A splice variant of the androgen receptor, AR-V7, confers resistance to AR-targeted therapies (ATTs) but not taxane chemotherapies in patients with metastatic castration-resistant prostate cancer. Since August 2015, a clinical-grade assay to detect AR-V7 messenger RNA expression in circulating tumors cells (CTCs) has been available to providers through a Clinical Laboratory Improvement Amendments–certified laboratory at Johns Hopkins University. Methods We contacted ordering providers of the first 150 consecutive tests by using a questionnaire-based survey to determine how the results of AR-V7 testing were used to influence clinical practice. Results In all, 142 (95%) of 150 questionnaires were completed by 38 providers from 29 sites across the United States and Canada. AR-V7 test results were reported either as CTC– (28%), CTC+/AR-V7– (30%), or CTC+/AR-V7+ (42%). Prevalence of AR-V7 detection increased with prior exposure to ATTs (abiraterone and enzalutamide naïve, 22%; after abiraterone or enzalutamide, 35%; after abiraterone and enzalutamide, 43%). Overall, management was affected by AR-V7 testing in 53% of the patients and even more often with CTC+/AR-V7+ results. AR-V7+ patients were commonly switched from ATT to taxane chemotherapy (43%) or were offered a clinical trial (43%); management remained unchanged in only 14% of these patients. Overall, patients who had a change in management on the basis of AR-V7 testing were significantly more likely to achieve a physician-reported 50% decline in prostate-specific antigen response on next-line therapy than those who did not change treatment (54% v 31%; P = .015). Conclusion Providers used AR-V7 testing to influence clinical decision making more often than not. Physicians reported that men with AR-V7+ results had the most treatment changes, and such men were preferentially managed with taxane therapy or offered a clinical trial, which may have improved outcomes.

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Quantitative and Qualitative Analysis of Blood-based Liquid Biopsies to Inform Clinical Decision-making in Prostate Cancer

European Urology ◽

10.1016/j.eururo.2020.12.037 ◽

2021 ◽

Author(s):

Irene Casanova-Salas ◽

Alejandro Athie ◽

Paul C. Boutros ◽

Marzia Del Re ◽

David T. Miyamoto ◽

...

Keyword(s):

Prostate Cancer ◽

Decision Making ◽

Qualitative Analysis ◽

Clinical Decision Making ◽

Clinical Decision ◽

Liquid Biopsies

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Beyond the Development of Health-Related Quality-of-Life (HRQOL) Measures: A Checklist for Evaluating HRQOL Outcomes in Cancer Clinical Trials—Does HRQOL Evaluation in Prostate Cancer Research Inform Clinical Decision Making?

Journal of Clinical Oncology ◽

10.1200/jco.2003.12.121 ◽

2003 ◽

Vol 21 (18) ◽

pp. 3502-3511 ◽

Cited By ~ 182

Author(s):

Fabio Efficace ◽

Andrew Bottomley ◽

David Osoba ◽

Carolyn Gotay ◽

Henning Flechtner ◽

...

Keyword(s):

Prostate Cancer ◽

Decision Making ◽

Clinical Trials ◽

Clinical Decision Making ◽

Clinical Decision ◽

Cancer Clinical Trials ◽

Health Related Quality ◽

Related Quality ◽

Health Related

Purpose: The aim of this study was to evaluate whether the inclusion of health-related quality of life (HRQOL), as a part of the trial design in a randomized controlled trial (RCT) setting, has supported clinical decision making for the planning of future medical treatments in prostate cancer. Materials and Methods: A minimum standard checklist for evaluating HRQOL outcomes in cancer clinical trials was devised to assess the quality of the HRQOL reporting and to classify the studies on the grounds of their robustness. It comprises 11 key HRQOL issues grouped into four broader sections: conceptual, measurement, methodology, and interpretation. Relevant studies were identified in a number of databases, including MEDLINE and the Cochrane Controlled Trials Register. Both their HRQOL and traditional clinical reported outcomes were systematically analyzed to evaluate their consistency and their relevance for supporting clinical decision making. Results: Although 54% of the identified studies did not show any differences in traditional clinical end points between treatment arms and 17% showed a difference in overall survival, 74% of the studies showed some difference in terms of HRQOL outcomes. One third of the RCTs provided a comprehensive picture of the whole treatment including HRQOL outcomes to support their conclusions. Conclusion: A minimum set of criteria for assessing the reported outcomes in cancer clinical trials is necessary to make informed decisions in clinical practice. Using a checklist developed for this study, it was found that HRQOL is a valuable source of information in RCTs of treatment in metastatic prostate cancer.

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