Ac-PSMA-617 RLT of chemotherapy-naïve patients with advanced metastatic prostate carcinoma led to a ≥ 90% decline in serum PSA in 82% of patients including 41% of patients with undetectable serum PSA who remained in remission 12 months after therapy. The remarkable therapeutic efficacy reported in this study could be achieved with reduced toxicity to salivary glands due to de-escalation of administered activities in subsequent treatment cycles. This necessitates further exploration for informing clinical practice and clinical trial design.

Metastatic prostate carcinoma overexpresses prostate-specific membrane antigen (PSMA), making this antigen a suitable target for radioligand therapy of the disease. Here we report on our experience with a series of 73 castration-resistant prostate carcinoma patients treated with 225 Ac-PSMA-617, identifying variables predictive for overall survival (OS) and progression-free survival (PFS) after 225 Ac-PSMA-617 treatment. Methods: 225 Ac-PSMA-617 was administered to patients who had metastatic castration-resistant prostate carcinoma and who had exhausted available therapy options for their disease. Full blood count, glomerular filtration rate, and liver function test were obtained at baseline and on follow-up for evaluation of toxicity. 68 Ga-PSMA PET/CT was obtained at baseline, before every treatment cycle, and on follow-up for selection of patients for treatment, to determine the activity of the treatment agent to be administered, and for response assessment. Serial prostatespecific antigen (PSA) was obtained for PSA response assessment. Results: Seventy-three men (mean age, 69 y; range, 45-85 y) with metastatic castration-resistant prostate carcinoma were treated with 210 cycles of 225 Ac-PSMA-617. In 70% of patients, a PSA decline of greater than or equal to 50% was obtained; 82% of patients had any PSA decline. In 29% of patients, all lesions on 68 Ga-PSMA PET resolved in response to treatment. During follow-up, 23 patients experienced disease progression, whereas 13 patients died from their disease. The estimated median PFS and OS were 15.2 mo (95% CI, 13.1-17.4) and 18 mo (95% CI, 16.2-19.9), respectively. In univariate analyses, factors such as baseline PSA, any PSA decline, PSA decline of greater than or equal to 50%, prior chemotherapy, prior radiation therapy, and baseline hemoglobin level were associated with longer PFS and OS (all Ps , 0.05). In multivariate analyses, there was a negative association between prior 177 Lu-PSMA therapy and PFS, and a positive association between PSA decline of greater or equal to 50% and PFS. Only a PSA decline of greater than or equal to 50% remained significantly associated with OS on multivariate analyses. Xerostomia was seen in 85% of patients but was not severe enough to warrant discontinuing treatment. Anemia was seen in 27 patients; no patients had grade IV bone marrow toxicity. Renal failure of grade III or IV was seen in 5 patients with baseline renal impairment. Conclusion: In this study, a PSA decline of greater than or equal to 50% after treatment with 225 Ac-PSMA-617 was proven by multivariate analyses to be significantly associated with OS and PFS. Furthermore, previous 177 Lu-PSMA treatment was negatively associated with PFS in both univariate and multivariate analyses.

Introduction: 225 Ac-PSMA-617, targeting the prostate-specific membrane antigen (PSMA) which is overexpressed on prostate cancer cells, has shown a remarkable therapeutic efficacy in heavily pre-treated metastatic castration-resistant prostate carcinoma patients. Here we report on treatment outcome and survival using this novel treatment modality in a series of 53 metastatic castration resistant prostate carcinoma patients directly following their androgen deprivation treatment.Patients and methods: 225 Ac-PSMA-617 was administered to 53 mCRPC patients directly following their androgen deprivation therapy. 68 Ga-PSMA PET/CT was obtained at baseline, before every treatment cycle and on follow-up for selection of patients for treatment, to determine the activity to be administered and for response assessment. Serial prostate specific antigen (PSA) was obtained for PSA response assessment. Results:The median age of the patient population under study was 63.4 yrs (range 45-83 years).A total number of 167 cycles were administered. The median number of cycles administered was 3 (range 1-7). Forty-eight patients (91%) had a PSA decline > 50%, and 51 patients (96%) had any decline in PSA . 68 Ga-PSMA-PET images became negative in 30 patients. In the multivariate analysis a PSA decline > 50 % proved predictive of both PFS and OS whereas platelet count also proved predictive for PFS. Median estimated OS for patients with a PSA decline < 50% was 9 months whereas the median OS of those patients with a PSA decline > 50% was not yet reached at the date of latest follow-up (55 months). Estimated median PFS for patients with a PSA decline > 50% was 22 months whereas that for patients with a PSA decline < 50% was 4 months. No severe of hematotoxicity was noted, whiles only 3 patients had grade III-IV nephrotoxicity. The commonest toxicity seen was grade I-II xerostomia observed in 81% of patients. Conclusion:In this series on 53 patients suffering from mCRPC, treatment with 225 Ac-PSMA-617 administered immediately following ADT, resulted in a > 50% decrease in PSA level in 91% of the patients. Furthermore, a PSA decline of greater than or equal to 50% proved the single most important factor predicting PFS and OS following 225 Ac-PSMA-617 treatment. Of interest, median OS of those patients with a PSA decline > 50% was not yet reached at the date of latest follow-up (55 months). These very favorable results obtained suggest a prospective randomized study comparing 225 Ac-PSMA-617 to current standard of care treatment options, e.g. enzalutamide, abiraterone acetate and docetaxel, post ADT is of major clinical relevance.