TPS238 Background: Metastatic prostate cancer is usually dependent on the androgen receptor (AR) pathway. However, around 20% of metastatic prostate cancers are AR independent with an aggressive behavior. Aggressive Variant mCRPC (AVPC) is considered a distinct entity and it has been defined by seven clinical-pathological criteria (AVPC-C). These tumors have poor response rates to conventional treatments and increased sensitivity to platinum-based combinations. Carboplatin (CBDCA) and cabazitaxel is a recommended regime in this scenario (Corn PG. Lancet Oncol 2019). These tumors are excluded from many mCRPC clinical trials and treatment options remain an unmet medical need. Methods: This is a multicentre, single-arm, phase 2 study that will investigate the activity of the combination of CBDCA, cabazitaxel and pembrolizumab in patients with AVPC. Patients will receive an induction phase consisting of 6 cycles of CBDCA area under the curve (AUC) 4 plus cabazitaxel 25mg/m 2 plus pembrolizumab 200mg on day 1 of each 3-week cycle. After induction, a maintenance phase will follow, with pembrolizumab 400mg administered every 6 weeks for 15 cycles or a total of 2 years. An initial cohort of 6 patients will be treated for an initial safety assessment. If ≤ 1 DLTs are observed an additional 36 patients will be enrolled at the same doses. Key eligibility criteria include at least 1 of the AVPC-C: histologically proven small cell or neuroendocrine differentiation, exclusive visceral metastases, predominantly lytic bone metastases (investigator criterion), bulky lymph nodes (≥ 5 cm in longest dimension) or high grade pelvic/prostatic masses, low PSA (≤10 ng/ml) at diagnosis in the presence of extensive disease (≥20 metastases), elevated serum LDH (≥2 x ULN) or CEA (≥2 x ULN) and time to castration resistance ≤6 months. Prior therapy with docetaxel and/or novel hormonal agents is allowed. The primary endpoint is 6-months radiographic progression-free survival (rPFS), by Prostate Cancer Working Group 3 (PCWG3) criteria and secondary endpoints are 12-months rPFS; response rate and PSA response by PCWG3, PSA PFS, overall survival and safety. A sample size of 42 patients achieves 80% power at a 0.05% significance level to detect an improvement of 20% in 6m-PFS. Imaging tumor assessments with CT scans and bone scintigraphy, and PSA will be done every 6 weeks in the first 24 weeks, every 12 weeks after first 24 weeks and at the end of treatment (EOT). Correlative studies will evaluate exploratory biomarkers as potential predictive/prognostic factors. Assessments include blood samples at baseline, 12 weeks after starting treatment, at the end of chemotherapy and at the EOT. Baseline FFPE tissue will be collected if obtained in the previous 12 months, or newly obtained tumor biopsy. This study was approved by a Central Institutional Review Board. Clinical trial information: NCT05563558 .