CARPET trial: A phase II trial evaluating trastuzumab deruxtecan in metastatic castration-resistant prostate cancer.

Abstract

TPS303 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge, as standard therapies, including androgen receptor pathway inhibitors, such as abiraterone and enzalutamide, yield limited responses. Human epidermal growth factor receptor 2 (HER2) is overexpressed in 60–70% of mCRPC cases but is often under diagnosed because it occurs without gene amplification or mutation and is not detected by next-generation sequencing. Immunohistochemistry (IHC) is more appropriate for identifying HER2 expressing tumors. Trastuzumab deruxtecan (T-DXd), a HER2-targeted antibody-drug conjugate, has shown efficacy in other HER2-positive (IHC 3+) solid tumors and has received tumor-agnostic approval from the FDA; however, its role in mCRPC is unclear. Previous clinical trials, including DESTINY-PanTumor02, have excluded prostate cancer, though recent case reports show promising responses in HER2+ mCRPC (PMID: 39496182, 40638235). Methods: CaRPET (NCT06610825) is a Phase II, open-label, single-arm, multi-center clinical trial evaluating the efficacy and safety of T-DXd in patients with HER2-positive (IHC 1+, 2+, or 3+) mCRPC who progressed on androgen deprivation therapy (ADT), novel hormonal agents, and taxane-based chemotherapy or were ineligible for taxanes. Eligible patients must have pathologically confirmed prostate adenocarcinoma, mCRPC with serum testosterone <50 ng/dL, documented progression after novel anti-androgens and taxanes (or taxane ineligibility), ongoing ADT, ECOG performance status 0–1, left ventricle ejection fraction ≥50%, and adequate organ function. HER2 status is determined using a prostate-cancer-specific IHC scoring system developed in our center accounting for intra- and intertumoral heterogeneity of HER2 expression. Exclusion criteria include prior HER2-targeted therapy, significant coronary vascular disease, and history of interstitial lung disease or pneumonitis requiring steroids. Patients will receive 5.4 mg/kg T-DXd intravenously every 3 weeks for up to 2 years. The primary endpoint is objective response rate to T-DXd, with secondary endpoints including safety, progression-free survival, overall survival, and quality of life. Exploratory objectives include assessment of HER3 expression and development of liquid biopsy-based assays. Five of the planned 60 patients have been enrolled. Clinical trial information: NCT06610825 .