Clinically relevant bone metastases are a major cause of morbidity and mortality for prostate cancer patients. Distinct phenotypes are described: osteoblastic, the more common osteolytic and mixed. A molecular classification has been also proposed. Bone metastases start with the tropism of cancer cells to the bone through different multi-step tumor–host interactions, as described by the “metastatic cascade” model. Understanding these mechanisms, although far from being fully elucidated, could offer several potential targets for prevention and therapy. Moreover, the prognosis of patients is markedly influenced by skeletal-related events. They can be correlated not only with bone metastases, but also with “bad” bone health. There is a close correlation between osteoporosis—a skeletal disorder with decreased bone mass and qualitative alterations—and prostate cancer, in particular when treated with androgen deprivation therapy, a milestone in its treatment. Systemic treatments for prostate cancer, especially with the newest options, have improved the survival and quality of life of patients with respect to skeletal-related events; however, all patients should be evaluated for “bone health” and osteoporotic risk, both in the presence and in the absence of bone metastases. Treatment with bone-targeted therapies should be evaluated even in the absence of bone metastases, as described in special guidelines and according to a multidisciplinary evaluation.

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3587 Background: The combination of BRAF inhibitors (BRAFi) plus anti-EGFR antibodies is a new standard of care in V600E BRAF mutated (mut) metastatic colorectal cancer (mCRC). Nevertheless, resistance develops during the target therapy (TT). We designed the URBAN study, a translational prospective project, in order to identify possible primary and acquired resistance mechanisms. Methods: Patients (pts) with V600E BRAF mut mCRC treated with BRAFi + anti-EGFR +/- MEK inhibitors at Veneto Institute of Oncology were enrolled. Clinical data and liquid biopsy at baseline and progression were collected. The ctDNA derived from plasma was analyzed by the AVENIO expanded kit, a hybridization capture sequencing-based 77 genes pan-cancer assay contained in NCCN Guidelines. Survival outcomes were calculated using Kaplan–Meier curves, log-rank tests and univariate Cox regression models were also performed. The study is exploratory and no formal hypothesis has been postulated. Results: Forty consecutive V600E BRAF mut mCRC pts were enrolled. Median age was 63 years (42-77), 47.5% of pts were males. Right CRC were 65% and 20% were MSI-H. Only 5% of pts received TT after second line; doublet regimen was administered in 60% of pts while triplet in 40%. According to the mPFS of doublet arm in the BEACON trial (4.2 months, mo), our population was divided in responder (R), 24 (60%), and non-responder (NR), 16 (40%). In R vs NR group, mPFS was 9 vs 3.2 mo while mOS was 21.6 vs 10.7 mo, respectively. The V600E BRAF mut was detected in 85% of the pre-treatment plasma samples without statistically significant differences in the genomic alterations between R and NR groups, but there was a higher frequency of MET and EGFR amplification in NR group. At progression, the mutation of BRAF was lost in 2 cases in R group. After receiving TT, the most common acquired mutations involved RAS genes: 16 pts (40%) acquired at least one activating mutation in KRAS and/or NRAS. Among these, 9 pts showed multiple mutations of the same RAS gene probably due to both intra- and inter-lesional heterogeneities; none of these pts had MSI-H mCRC. We found a higher number of RAS and MAP2K1 acquired mutations in NR and a trend to acquire EGFR amplification in R group. Inactivating mutations in RFN43 gene was observed in 2 cases in R group. These data did not reach statistical significance, probably due to the low number of cases. Interestingly, 37% of NR pts acquired three or more molecular alterations vs 13% in R group. Furthermore, a higher number of genetic alterations was acquired in pts treated with doublet vs triplet regimen. Conclusions: This prospective, observational molecular profiling study provided further evidences to support the use of ctDNA in capturing the dynamic somatic mutational spectrum in V600E BRAF mut mCRC and to identify potential mechanisms of resistance to TT. An expansion of study population is ongoing.

218 Background: Immune checkpoint inhibitors (ICI) showed high efficacy in both first and subsequent lines in metastatic colorectal cancer with mismatch repair deficiency (dMMR-mCRC); however, they still fail in a minority of patients (pts). In non-preplanned analyses from previous studies, RAS mutations ( RASm) have been related to limited activity of ICI monotherapy (ICIm) as compared to ICI doublets (ICId) in dMMR-mCRC. Emerging data suggest different immunological features in presence of RASm, resulting in lower immunogenicity. Methods: NERDY is a retrospective, monocentric study designed to investigate the effect of ICIm and ICId on dMMR-mCRC basing on RASm. Pts with dMMR-mCRC treated with ICIm/ICId at our Institute were included. Clinical-pathological features for each patient were collected. On primary tumor specimens, proinflammatory pathways and CMS subgroup will be assessed by Nanostring and RNA-Seq respectively. The study is exploratory and no formal hypothesis has been postulated. Both PFS and OS were calculated with Kaplan-Meier. Cox proportional hazard model was adopted in the interaction tests. Primary objective was to assess OS and PFS according to RAS in dMMR-mCRC pts treated with ICIm or ICId. Secondary objectives were to describe the inflammatory infiltrate and TMB in dMMR-mCRC according to RAS status. Results: From June 2015 to January 2022, a total of 126 consecutive dMMR-mCRC pts treated with ICI were included, 33 RASm/93 RASwt. RASm pts were more frequently males (p=0.015) and younger (median age 47 vs 65). An imbalance was observed in sidedness (more right-CRC in RASwt than in RASm as BRAF effect, p=0.001) and timing of ICI (administered in later lines in RASm, p=0.013). No differences in ECOG-PS, histotype, disease burden, stage at diagnosis, treatment with ICIm vs ICId and best response. At a median follow up of 53.5 months (95%CI 34.7-56.9), a trend toward longer PFS in pts treated with ICId over ICIm was found in the overall population (HR 0.62; 95%CI 0.36-1.05; p=0.055), being significantly longer in RASm-only pts (HR 0.41; 95%CI 0.13-1.28; p=0.047) but not in RASwt-only pts (HR 0.64; 95%CI 0.34-1.20; p=0.139). No difference was observed in OS between ICId and ICIm in the overall population (HR 0.64; 95%CI 0.36-1.16; p=0.121), in RASwt (HR 0.59; 95%CI 0.29-1.20; p=0.132) nor in RASm pts (HR 0.59; 95%CI 0.19-1.78; p=0.275). Interaction test for RAS and ICI treatment type was not significant for PFS (HR 0.63; 95%CI 0.21-1.94; p=0.423) nor for OS (HR=1.00; 95%CI 0.29-3.41; p=0.999). Conclusions: Preliminary clinical results of the NERDY study suggest enhanced activity of ICId compared to ICIm in pts with RASm dMMR-mCRC. Further data are expected from pending translational analyses and a pre-planned adjunctive cohort from two other Italian centers will be used for external validation.