Liu, Glenn

162 Background: Clinical trial conduct in advanced prostate cancer has changed dramatically with the continued development of new imaging approaches, molecular phenotypes and genetic subtypes, prognosis assessments, and effective therapies across a range of disease states. This created a need to redefine terminology and best practices for clinical trials. Methods: We convened PCWG4, an international expert committee of multidisciplinary working groups, between 2016 and 2025 to update and expand PCWG2-3 recommendations based on emerging evidence and clinical trial data in an innovative biomarker and imaging context to provide guidance for clinical trial design, eligibility, and endpoint assessments. Results: PCWG4 redefines terminology around disease states and prior therapies in a patient-centric context, considering imaging modalities, with a particular focus on PET-defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, imaging and non-imaging-based responses. We define delay/prevent endpoints including responses by pathology, ctDNA, circulating tumor cells, and PSA declines, and specify intervals for re-assessments including imaging, biomarker assessments, and patient reported outcomes. We propose new imaging-specific rPFS criteria including guidance with serial PSMA PET/CT imaging (Table). We provide recommendations in a biomarker-based context for the indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. Conclusions: PCWG4 expands guidance on patient and tumor profiling, as well as therapy development, to include both androgen deprivation therapy sensitive and resistant settings, reflecting today’s more heterogeneous and diverse patient population to optimize outcomes. PCWG4-defined radiographic progression by imaging modality for patients with metastatic disease. Pretreatment Scan On-treatment Scan #1(≥week 8) On-treatment Scan #2 All Subsequent Scans Bone scintigraphy Comparator Comparator for subsequent scansPOD never called here POD:PCWG3 criteria (2+2 additional new lesions) POD:≤5 new lesions: PCWG3 criteria 2 new lesions confirmed≥6 new lesions CT/MRI Any measurable disease Comparator PCWG3/RECIST PCWG3/RECIST PCWG3/RECIST PSMA PET Bones, and lymph nodes and lung metastases (non-RECIST qualifying by + on PET only) Comparator POD:≤5 new lesions: 2 new lesions confirmed on a subsequent scan≥6 new lesions Same as prior Same as prior Liver and non-pulmonary viscera Comparator POD:Any single new lesion that represents disease Same as prior Same as prior

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

AbstractBackgroundE3805 (CHAARTED) is a phase 3 trial demonstrating improved survival for men with metastatic hormone‐sensitive prostate cancer (mHSPC) randomized to treatment with docetaxel (D) and androgen‐deprivation therapy (ADT) versus ADT alone. We assessed the association of baseline body mass index (BMI) and metformin exposure with quality of life (QOL) and prostate cancer outcomes including survival in patients enrolled in the CHAARTED study.MethodsWe performed a posthoc exploratory analysis of the CHAARTED trial of men with mHSPC randomized to treatment with ADT with or without D between 2006 and 2012. Cox proportional hazards models and Kruskal–Wallis test were used to evaluate the association between BMI with QOL and prostate cancer outcomes and between metformin exposure and survival.ResultsIn 788 of 790 enrolled patients with prospectively recorded baseline BMI and metformin exposure status, lower BMI was not associated with survival, but was associated with high volume disease (p < 0.0001) and poorer baseline QOL on functional assessment of cancer therapy–prostate (p = 0.008). Only 68 patients had prevalent metformin exposure at baseline in the CHAARTED trial. Four groups were identified: ADT + D + metformin (n = 39); ADT + D (n = 357); ADT + metformin (n = 29); and ADT alone (n = 363). Baseline clinicopathologic characteristics were similar between groups. In this small exploratory multivariable analysis, metformin exposure was not associated with survival (hazard ratio: 1.15; 95% confidence interval: 0.81–1.63, p = 0.44).ConclusionsThere was no link between baseline BMI and survival, but lower baseline BMI was associated with features of greater cancer burden and poorer QOL.

149 Background: Patients with metastatic hormone-sensitive prostate cancer (mHSPC) have a variable response to ADT and some benefit from the addition of docetaxel or an androgen signaling pathway inhibitor. We found that loss of the epigenetic regulator KDM5D is associated with more aggressive prostate cancer (PC). We sought to determine whether MYBL2 which is regulated by KDM5D mediates this effect. MYBL2 is a transcription factor which controls key genes (e.g. FOXM1) and increases cell cycle progression and survival. Methods: AR expressing hormone-sensitive cell lines, LNCaP and LAPC4 were used. Motif analysis and CHiPseq of LNCaP with and without siKDM5D was performed and impact of modulation of KDM5D and MYBL2 in both cells on cell survival was assessed. Gene expression profiling (GEP) data assessed MYBL2’s association with KDM5D levels in localized disease (publicly available data) and mHSPC (Decipher whole Affymetrix platform on CHAARTED samples). Results: Silencing KDM5D increased H3K4me3 and increased MYBL2 expression. GEP showed a strong negative correlation between KDM5D and MYBL2 in patients with localized PC (-0.66; TCGA) but not from primary prostate cancer tissue with mHSPC (-0.03; CHAARTED). Cells with low KDM5D and high MYBL2 were androgen independent and more resistant to docetaxel. In TCGA, patients with high MYBL2 had a higher rate of relapse from localized disease. In patients with metastatic disease (CHAARTED) low MYBL2 was associated with a better overall survival (OS) on multivariable analysis when treated with ADT or ADT + docetaxel. Conclusions: Low MYBL2 is associated with a longer OS with ADT alone and ADT and docetaxel independent of clinical variables. Patients with high MYBL2 expression had better OS with ADT plus docetaxel compared with patients with high MYBL2 treated with ADT alone.[Table: see text]

Purpose In April 2017, the American Urological Association, American Society for Radiation Oncology, and Society of Urologic Oncology released a joint evidence-based practice guideline on clinically localized prostate cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. Methods The Clinically Localized Prostate Cancer guideline was reviewed for developmental rigor by methodologists. An ASCO Expert Panel then reviewed the content and the recommendations. Results The ASCO Expert Panel determined that the recommendations from the Clinically Localized Prostate Cancer guideline were clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the Clinically Localized Prostate Cancer guideline except for two recommendations on cryosurgery. The two recommendations covering cryosurgery were not endorsed because the panel found that there is insufficient evidence to support the use of cryotherapy in this setting. Recommendations The ASCO Expert Panel endorsed all but two of the original guideline recommendations as written and offered a series of discussion points to guide practice.

181 Background: To evaluate whether metformin (Met) a widely-used, nontoxic oral antidiabetic drug with putative anticancer properties leads to improvements in prostate cancer (PC) outcomes in the CHAARTED trial. Methods: In the CHAARTED database where metformin use at baseline was recorded prospectively, we identified patients with metastatic PC who underwent either ADT alone or ADT and docetaxel (D) chemotherapy. Cox proportional hazards models were used to determine the effect of Metformin on outcomes. Results: A total of 788 patients (median age, 63 y) had complete data after randomization. Comparison of ADT+D+Met (n = 39) to ADT+D (n = 357) and ADT+Met (n = 29) to ADT alone (n = 363) revealed similar clinicopathologic characteristics. Cause of death was PC in 13(81%) of ADT+D+Met, 72(85%) ADT+D, 9(82%) ADT+Met and 105(84%) ADT alone groups. See table for PC outcomes and overall survival by metformin use. Cox regression analysis for overall survival stratified by stratification factors at randomization demonstrates Met use was associated with a trend for worse overall survival (HR 1.47 95%CI: [0.95,2.26], p = 0.08) with adjustment for treatment arm and prior local therapy. In contrast, ADT+D use (HR 0.62; 95%CI: [0.47,0.81]) and prior local therapy with surgery or radiation (HR 0.56; 95% CI: [0.38, 0.82]) were associated with improved survival. Conclusions: In this study, baseline metformin did not improve PC outcomes. Partial support and drug supply by Sanofi. Clinical trial information: NCT00309985. [Table: see text]

137 Background: Prior work from SWOG 9346 revealed that PSA ≤ 0.2 ng/dL at 7 months (mo) is prognostic for longer OS with ADT alone. We sought to evaluate if this optimal decline remained predictive of better OS when D was added to ADT for initial mHSPC treatment. Methods: We performed a landmark survival analysis at 7 mo using the E3805 database (NCT00309985). Inclusion required at least 7 mo of followup and PSA levels at 7 mo from ADT initiation. Survival was defined from ADT start or randomization to death. SWOG 9346 PSA nadirs of ≤ 0.2, > 0.2-4 and > 4 were used as classifiers. Results: 719 patients were eligible for analysis: 358 treated with ADT plus D and 361 with ADT alone. Median follow-up was 23.1 mo. On multivariable analysis (MVA), achieving a PSA ≤ 0.2 at 7 mo was more likely if the patient received D and had lower volume disease, prior local therapy, and lower baseline PSAs (all p ≤ 0.01). Across all patients, median OS was significantly longer if PSA at 7 mo reached ≤ 0.2 compared to > 4 (p < 0.0001) (Table). On MVA, PSA ≤ 0.2 at 7 mo and low volume disease were prognostic of longer OS (all p < 0.01). On ADT, 28.8% achieved a PSA ≤ 0.2 at 7 mo vs. 45.3% on ADT+D. Patients on ADT alone who achieved a PSA nadir ≤ 0.2 had the best survival. These patients were more likely to have low volume disease (56.7%) compared to the ADT + D pts (46.3%). Conclusions: Achieving PSA ≤ 0.2 at 7 mo remains prognostic for longer OS with ADT for mHSPC, whether administered alone or with D. Adding D to ADT increased the likelihood of a lower PSA and improved survival. Partial support and drug supply by Sanofi. Clinical trial information: NCT00309985. [Table: see text]