BackgroundThe early identification of responsive and resistant patients to androgen receptor-targeting agents (ARTA) in metastatic castration-resistant prostate cancer (mCRPC) is not completely possible with prostate-specific antigen (PSA) assessment and conventional imaging. Considering its ability to determine metabolic activity of lesions, positron emission tomography (PET) assessment might be a promising tool.Patients and methodsWe carried out a monocentric prospective study in patients with mCRPC treated with ARTA to evaluate the role of different PET radiotracers: 49 patients were randomized to receive 11C-Choline, Fluorine 18 fluciclovine (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid - FACBC) (18F-FACBC), or Gallium-68-prostate-specific-membrane-antigen (68Ga-PSMA) PET, one scan before therapy and one 2 months later.The primary aim was to investigate the performance of three novel PET radiotracers for the early evaluation of response to ARTA in metastatic CRPC patients; the outcome evaluated was biochemical response (PSA reduction ≥50%). The secondary aim was to investigate the prognostic role of several semiquantitative PET parameters and their variations with the different radiotracers in terms of biochemical progression-free survival (bPFS) and overall survival (OS).The study was promoted by the Italian Department of Health (code RF-2016-02364809).ResultsRegarding the primary endpoint, at log-rank test a statistically significant correlation was found between metabolic tumor volume (MTV) (P = 0.018) and total lesion activity (TLA) (P = 0.025) percentage variation among the two scans with 68Ga-PSMA PET and biochemical response. As for the secondary endpoints, significant correlations with bPFS were found for 68Ga-PSMA total MTV and TLA at the first scan (P = 0.001 and P = 0.025, respectively), and MTV percentage variation (P = 0.031). For OS, statistically significant correlations were found for different 68Ga-PSMA and 18F-FACBC parameters and for major maximum standardized uptake value at the first 11C-Choline PET scan.ConclusionsOur study highlighted that 11C-Choline, 68Ga-PSMA, and 18F-FACBC semiquantitative PET parameters and their variations present a prognostic value in terms of OS and bPFS, and MTV and TLA variations with 68Ga-PSMA PET a correlation with biochemical response, which could help to assess the response to ARTA.

Identifying biomarkers for mRCC is an unmet need in actual immunotherapy (IO) era. Available data regarding chromosome 3p-related genes (i.e., VHL, PBRM1, SETD2) as potential predictors for therapy response is conflicting. We describe the correlation of these GA with clinical outcomes in mRCC pts treated with IO/IO or IO/tyrosine kinase inhibitor (TKI). We performed a single-center retrospective analysis on mRCC pts treated with first line IO/IO or IO/TKI. A multi-gene panel was used, allowing the amplification of 841 amplicons (54.93kb, human reference sequence hg19/GRCh37) in the coding sequences of the following genes: ATM, BAP1, KDM5C, MET, MTOR, NF2, PBRM1, PIK3CA, PTEN, SETD2, SMARCB1, TP53, TSC1, TSC2, VHL. 30 mRCC pts undergoing IO/IO and IO/TKI were included. Of these, 18 had tumor tissue adequate for molecular analysis: 77.8% male, 22.2% female. Histology was 100% clear cell. IMDC risk was 50% intermediate, 33.4% good, 16.6% poor. First line therapy was 89% IO/TKI, 11% IO/IO. 83.3% pts (n=15) carried GA, among which 61.1% had a known pathogenic mutation (PAT). Most common GA included VHL in 44% (n=8; 7 PAT and 1 variant of unknown significance - VUS), PBRM1 in 44% (n=8; 5 PAT and 3 VUS) and SETD2 in 33% (n=6; 4 PAT and 2 VUS). With the limit of a small sample that did not allow proper statistical analyses, SETD2 mutated pts had lower median progression free (mPFS) and overall survival (mOS) than non-SETD2 mutated pts. Higher mPFS and mOS were shown with VHL or PBRM1 GA, especially in PBRM1+VHL mutated pts (Table). Of note, all PBRM1+VHL mutated pts underwent IO/TKI.Table 24PmPFS (months)mOS (months)MutatedNon-mutatedMutatedNon-mutatedSETD21214.51516VHL19112014PBRM1197.52013PBRM1+VHL207.520.513.5 Open table in a new tab Our data shows a possible negative predictive role of SETD2 GA for IO-based therapy in RCC. Concomitant VHL and PBRM1 GA could act as a predictor for IO/TKI efficacy. Our hypothesis-generating analysis highlights the need of an integrated evaluation of these genes as promising biomarkers in RCC. Further larger studies are required.