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Prostate specific membrane antigen (PSMA)-targeted radionuclide therapies (PSMA-TRTs) is one of the most promising treatments for metastatic castration-resistant prostate cancer (mCRPC) upon progression on androgen receptor signaling inhibitors (ARPi). However, recent studies show that only about half of patients respond to PSMA-TRTs. Expression of PSMA on cancer cells via PET-imaging is of some use as a predictive biomarker of response to PSMA-TRTs, but there are patients with strong PSMA imaging who do not respond and some with poor PSMA imaging that do respond. PSMA imaging does not fully capture response predictability. Currently, the lack of predictive biomarkers of response limits optimal selection of the patient population most likely to benefit from to PSMA-TRTs. PSMA-TRTs radionuclides emit α or β radiations, which induce DNA damage in targeted cells, followed by immunogenic cell death (ICD), evidenced by calreticulin (CRT) plasma membrane accumulation. To investigate the role of PSMA expression and CRT membrane localization as a biomarker of response to PSMA-TRT, we isolated circulating tumor cells (CTCs) from patients with mCRPC, enrolled in a phase I dose escalation trial of 225Ac-J591 (NCT03276572). Thirty-two (32) patients were enrolled (median age 69. 5, range 52-89; PSA 149.1, range 4.8-7168); 78% and 68% of patients received ≥ 2 prior ARPi treatments or chemotherapy, respectively. 69% and 44% of patients experienced any or >50% PSA decline, respectively, with a median PFS of 5.1 months and median OS of 11.1 months. CTCs were isolated before treatment (baseline) from 30/32 of enrolled patients, and 12 weeks after treatment initiation (on-treatment) from 21/32 patients. Enriched CTCs via CD45 depletion were subsequently immunostained for cytokeratin (CK, standard epithelial marker), CD45 (standard marker to identify contaminating leukocytes), PSMA, calreticulin (CRT) and DAPI. CTCs were subjected to multiplex confocal microscopy and identified as CK+/CD45-/DAPI+ cells. For each patient, at each time point, the following parameters are scored: i) total number of CTCs, ii) number of PSMA+ CTCs, iii) number of CRT+ CTCs, iv) number of CTCs with plasma membrane CRT decoration. Percent of PSMA+ CTC at baseline and changes in percentage of CRT+ CTCs and CTCs with plasma membrane CRT decoration between baseline and on treatment timepoints are correlated with clinical response and time to progression upon 225Ac-J591 treatment. Our preliminary results indicate higher expression of plasma membranous CRT in on-treatment CTCs in responders (PFS>12 months; n= 39 CTCs from 3 patients) than in non-responders (PFS Citation Format: Giuseppe Galletti, Prerna Vatsa, Joseph R. Osborne, Neil H. Bander, David M. Nanus, Scott T. Tagawa, Paraskevi Giannakakou. CTC-based biomarker analysis and correlation with clinical response to PSMA-TRT in mCRPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1264. |
