CHICAGO, IL USA (UroToday.com) - Dr. Howard Scher of Memorial Sloan Kettering presented the Prostate Cancer Working Group 3 (PCWG3) Consensus Guidelines, an update from the previously published Prostate Cancer Working Group 2 (PCWG2) set published in 2008. The previous set outlined key principles of trial conduct, including authenticating disease progression prior to beginning therapy, expanding the definition of tumor response from RECIST to include reporting changes in each disease manifestation separately, ensuring drugs are not stopped prematurely due to slow PSA increase when the change is not clinically meaningful, and establishing the “2+2” rule that distinguishes bone scan “flare” from actual disease progression, a rule that has been used in phase 3 clinical trial development. The PCWG2 guidelines were based upon the castration-resistant prostate cancer (CRPC) disease framework that focused on a pre- or post- docetaxel clinical state, a framework that is less meaningful in the current treatment landscape.
PCWG3 sought to meet several key objectives, and included a diverse group of 32 experts in the treatment of advanced prostate cancer. PCWG3 attempted to identify subsets of patients that would have the best response to therapy, and those who may have specific contraindications to various treatments. It also sought to develop intermediate endpoints to be used in clinical trials to show treatment effects more reliably and might support regulatory submissions. The investigators defined a method for assessing changing biology before and after treatment in a way that they hope may predict sensitivity or resistance to treatment. Finally, PCWG3 sought to demonstrate how to best use the available agents to maximize patient outcomes, including methods that involved sequential or combinations of therapies. Ultimately it attempted to provide recommendations for best practices at each stage of clinical trial development, including defining eligibility criteria and clinical or molecular phenotypes for risk stratification, defining disease assessment methods based on the mechanism of action of a given therapeutic, describing outcomes of importance, including new outcomes like metastasis-free and progression-free survival and symptomatic skeletal events, and identifying methods to distinguish when treatment beyond progression would benefit the patient vs when it was more beneficial to stop therapy.
The PCWG3 recommended several revisions to update PCWG2 guidelines. In terms of eligibility for studies, the team suggested doing away with previous classifications of pre- or post-docetaxel patients in favor of describing which lines of therapies patients had already received, including start and stop dates and information regarding prior response to treatment. They also reiterated the importance of defining histologic subtypes, particularly the adenocarcinoma vs small cell phenotypes. Re-biopsy, if the patient agrees, is recommended to clarify the histology and to perform a biologic characterization of the metastatic site.
In addition, the PCWG3 also defined best imaging practices. They again noted that CT or MRI of the abdomen and pelvis, plus bone scan, are the standard imaging modalities in prostate cancer. Other modalities, including FDG-PET or sodium fluoride PET, remain investigational. Subtypes of disease were redefined as follows: 1) Local, including regional lymph nodes, 2) Node-only spread, 3) Bone +/- lymph node spread, and 4) Visceral spread, having the worst prognosis of all metastatic sites. M0, or non-metastatic disease, was again included, as was the transition to M1, or metastatic disease.
In terms of defining interventions and outcomes for this cohort of men with advanced prostate cancer, the investigators defined several key points. Prior to studying interventions in humans, PCWG3 suggests using pharmacodynamic measures to confirm the mechanism of action of a given medication. Second, the group advocated for optimization of dose and schedule of investigational drugs based on readily available biologic markers and safety, rather than relying solely on safety. The PCWG3 also suggested determining the type and timing of anticipated antitumor effects, a priori, and to perform measurements for tumor assessment at fixed intervals in ways that were rational. Recommendations for outcomes were similar between PCWG2 and PCWG3 as they suggest assessing for clinical benefit, or cessation of disease progression, and PCWG3 suggests also following the development of symptomatic skeletal events. PCWG3 members advocate validation of all biomarkers and imaging modalities for future clinical trial monitoring.
PCWG3 sought to streamline PCWG2 recommendations where possible and to improve the integrity of the recommendations by validating all biomarkers and imaging modalities. Based on the development of new treatments for advanced prostate cancer, the recommendations regarding measurement of progressive disease or response to therapy continue to be assessed. In time it is likely that the PCWG3 recommendations will heavily influence the development of clinical trials for M0 and M1 patients with CRPC.
Presented by Howard I. Scher, MD at the American Society of Clinical Oncology (ASCO) Annual Meeting - Illumination & Innovation: Transforming Data into Learning - May 29 - June 2, 2015 - Chicago, Illinois USA
Memorial Sloan Kettering Cancer Center, New York, NY USA
Written by Alicia K. Morgans, MD, assistant professor of medicine and medical oncologist at Vanderbilt-Ingram Cancer Center, and medical writer for UroToday.com