The ARPI Treatment-Emergent “Phenotypic flip” on [18F]F-FDG, [68Ga]Ga-FAPI-04, and [68Ga]Ga-PSMA-11 PET/CT in Metastatic Dedifferentiated Small Cell Cancer of Prostate: Potential for FAPI-Based Evaluation and Theranostics

Abstract

Prostate-specific membrane antigen (PSMA)-targeted imaging and therapy have greatly augmented prostate cancer management. However, potent androgen receptor pathway inhibitors (ARPIs) drive treatment-emergent small cell transformation of prostate cancer. This aggressive lineage plasticity suppresses PSMA expression, rendering standard PSMA positron emission tomography (PET)/computed tomography (CT) ineffective and necessitating alternative molecular imaging strategies. A 60-year-old male with metastatic prostate adenocarcinoma and a baseline serum prostate-specific antigen (PSA) of 629 ng/mL underwent [18F]F-PSMA-1007 PET/CT, revealing extensive PSMA expressing disease. He was treated aggressively with transurethral resection, bilateral orchidectomy, docetaxel, and ARPIs. Posttreatment, his serum PSA reduced to 0.99 ng/mL. Response assessment with [68Ga]Ga-PSMA-11 PET/CT demonstrated a marked reduction of PSMA expressing disease, falsely suggesting a favorable response on visual analysis. However, concurrent CT revealed a stark morphological progression, including new retroperitoneal lymphadenopathy and multiple bilobar liver metastases, confirming progressive disease as per the RECIP (Response Evaluation Criteria in PSMA PET/CT) 1.0 criteria. Suspecting treatment-emergent dedifferentiation, [18F]F-fluorodeoxyglucose (FDG)-PET/CT was performed, revealing intense hypermetabolism in all progressing lesions. To explore theranostic alternatives, [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 PET/CT was acquired, demonstrating robust stromal expression across the primary tumor, nodes, and bilobar liver metastases. A liver biopsy confirmed metastatic small cell carcinoma, positive for neuroendocrine markers and a Mib-1 index of 60%.

This case illustrates the “phenotypic flip” associated with ARPI resistance, highlighting a critical diagnostic pitfall, relying solely on PSMA expression can mask true morphological progression. Clinicians must maintain a high suspicion for dedifferentiation when a biochemical response contradicts CT findings. In PSMA-negative scenario, multimodality imaging is of paramount importance. While [18F]F-FDG-PET/CT accurately captures the altered metabolic burden, [68Ga]Ga-FAPI-04 PET/CT compliments by visualization of the tumor stroma. Intense FAP expression confirms the extent of dedifferentiated clones and establishes a viable target for emerging FAPI-directed theranostics.