Automated radiolabeling and handling of 177 Lu- and 225 Ac-PSMA-617 using a robotic pipettor.

While automated modules for F-18 and C-11 radiosyntheses are standardized with features such as multiple reactors, vacuum connection and semi-preparative HPLC, labeling and processing of compounds with radiometals such as Zr-89, Lu-177 and Ac-225 often do not require complex manipulations and are frequently performed manually by a radiochemist. These procedures typically involve transferring solutions to and from vials using pipettes followed by heating of the reaction mixture, and do not require all the features found in most commercial automated synthesis units marketed as F-18 or C-11 modules. Here we present an efficient automated method for performing radiosyntheses involving radiometals by adapting a commercially available robotic pipettor originally developed for high-throughput processing of biological samples. While a robotic pipettor is less costly than a radiosynthesis module, it holds many similar advantages over manual radiosynthesis such as minimization of operator error, lower operator exposure rates, and abbreviated synthesis times, among others. To demonstrate the feasibility of using the OpenTrons OT-2 robotic pipettor to perform automated radiosyntheses, we radiolabeled and formulated 177 Lu-PSMA-617 and 225 Ac-PSMA-617 on the system. The OT-2 was then used to help streamline the quality control process for both products, further minimizing manual handling by and exposure to the radiochemist.

225 Ac-PSMA-617-targeted alpha therapy for the treatment of metastatic castration-resistant prostate cancer: A systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to present an overview of the role of 225 Ac-PSMA (prostate-specific membrane antigen)-targeted alpha therapy (TAT) as a salvage treatment option in metastatic castration-resistant prostate cancer. METHODS: A systematic literature review was performed in databases such as Medline, Embase, PubMed, Cochrane Central Register of Controlled Clinical Trials, and the website; www.ClinicalTrials.gov until December 2020. The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. All original articles, including retrospective, prospective, hand-searched articles, and clinical trials, were searched, and appropriate data were included for the analysis. The study's primary endpoint assessed therapeutic efficacy by biochemical response assessment criteria (any prostate-specific antigen [PSA] decline and >50% PSA decline from the baseline) after 225 Ac-PSMA-TAT. The secondary endpoints included assessing overall survival (OS), progression-free survival (PFS), molecular response, and therapy-related adverse events across all the studies. The values were expressed as pooled proportions and demonstrated graphically by forest plots using the random-effects model. RESULTS: After the data extraction and filtration process, a total of three publications, including 141 patients, were included for the final analysis. The pooled proportion of patients demonstrating any PSA decline and greater than 50% PSA decline were 83% (95% confidence interval [CI]: 77%-89%) and 59% (95% CI: 42%-76%), respectively. The pooled proportions for OS was 81% (95% CI: 74%-89%). The pooled proportion of patients who have shown complete molecular response are 17% (95% CI: 5%-29%). The median PFS was 12 months (interquartile range: 8.2-14.4 months). Across the studies, the most common side effects from 225 Ac-PSMA-617 TAT were xerostomia/dry mouth, which pertained to Gr I-II in 63.1% (89 of 141), followed by fatigue in 44.5% (45 of 101) of patients. Grade I-II and III anemia was noted in 48.5% (49 of 101) and 6% (6 of 101), respectively. Grade III leukopenia and thrombocytopenia were negligible: 0.9% (1 of 101) and 0.9% (1 of 101), respectively. Similarly, grade III nephrotoxicity was also observed only in 5 of 101 (5%) patients. CONCLUSION: Treatment with 225 Ac-PSMA-617 TAT demonstrated biochemical response, improved survival, caused low treatment-related toxicity proving a promising salvage treatment option in mCRPC patients.

68Ga-Prostate-specific membrane antigen (psma) positron emission tomography (pet) in prostate cancer: a systematic review and meta-analysis.

INTRODUCTION: Prostate cancer (PC) is the second most commonly diagnosed cancer in males. 68Ga-PSMA PET/CT, a non-invasive diagnostic tool to evaluate PC with prostate-specific membrane antigen (PSMA) expression, has emerged as a more accurate alternative to assess disease staging. We aimed to identify predictors of positive 68Ga-PSMA PET and the accuracy of this technique. MATERIALS AND METHODS: Diagnostic accuracy cross-sectional study with prospective and retrospective approaches. We performed a comprehensive literature search on PubMed, Cochrane Library, and Embase database in search of studies including PC patients submitted to radical prostatectomy or radiotherapy with curative intent and presented biochemical recurrence following ASTRO 1996 criteria. A total of 35 studies involving 3910 patients submitted to 68-Ga-PSMA PET were included and independently assessed by two authors: 8 studies on diagnosis, four on staging, and 23 studies on restaging purposes. The significance level was α=0.05. RESULTS: pooled sensitivity and specificity were 0.90 (0.86-0.93) and 0.90 (0.82-0.96), respectively, for diagnostic purposes; as for staging, pooled sensitivity and specificity were 0.93 (0.86-0.98) and 0.96 (0.92-0.99), respectively. In the restaging scenario, pooled sensitivity and specificity were 0.76 (0.74-0.78) and 0.45 (0.27-0.58), respectively, considering the identification of prostate cancer in each described situation. We also obtained specificity and sensitivity results for PSA subdivisions. CONCLUSION: 68Ga-PSMA PET provides higher sensitivity and specificity than traditional imaging for prostate cancer.

225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience.

PURPOSE: Up to 30% of patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) never respond or develop resistance to 177Lu-labeled PSMA-targeted radioligand monotherapy. Single-agent PSMA-targeted radioligand therapy (PRLT) with the alpha-emitter 225Ac showed promise against mCRPC but may cause severe and/or persistent xerostomia, which may substantially impair patients' quality-of-life. We hypothesized that when 177Lu-PSMA ligand alone is ineffective, tandem therapy with low-activity 225Ac-PSMA ligand plus full activity of the beta emitter may enhance efficacy while minimizing xerostomia severity. METHODS: We retrospectively analyzed pilot experience with 1 course of 225Ac-PSMA-617/177Lu-PSMA-617 tandem therapy in our first 20 patients with mCRPC receiving this intervention after insufficiently responding to 177Lu-PSMA-617 monotherapy. This cohort had late-stage/end-stage disease with high baseline prostate-specific antigen (PSA) concentration (median 215 ng/mL), heavy pre-treatment (abiraterone and/or enzalutamide, and 177Lu-PRLT [median cumulative activity, 26.3 GBq] in 20/20 patients, 100%; docetaxel and/or cabazitaxel in 13/20 patients, 65%), and frequent Eastern Cooperative Oncology Group performance status of 2 (8/20 patients, 40%). RESULTS: Median (minimum-maximum) administered activities were 225Ac-PSMA-617, 5.3 (1.5-7.9) MBq, and 177Lu-PSMA-617, 6.9 (5.0-11.6) GBq. Significant responders to tandem therapy received 177Lu-PSMA-617 monotherapy as maintenance (median [minimum-maximum]: 1 [0-5] cycle). After a median (minimum-maximum) 22 (14-63) weeks' follow-up, 13/20 patients (65%) had as best biochemical response a PSA decline > 50%. Median (95% confidence interval) progression-free survival was 19 (12-26) weeks, and overall survival was 48 (4-92) weeks post-tandem therapy administration. Xerostomia was reported as grade 1 (very mild) in 8/20 patients (40%), grade 2 (mild) in 5/20 (25%), and grade 3/4 in 0/20. CONCLUSIONS: Our results suggest that a single course of tandem therapy with low-activity 225Ac-PSMA-617/full-activity 177Lu-PSMA-617 may safely enhance response to PRLT in men with late-stage/end-stage mCRPC while minimizing xerostomia severity. Formal study of this combination is warranted.

Efficacy and Safety of 225Ac-PSMA-617-Targeted Alpha Therapy in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: To conduct a meta-analysis of the efficacy and safety of 225Ac-PSMA-617 in the treatment of metastatic castration-resistant prostate cancer based on existing clinical evidence. METHODS: Search for retrospective studies about 225Ac-PSMA-617 in the treatment of metastatic castration-resistant prostate cancer from establishment to July 2021 in PubMed and EMBASE. The primary endpoint was 225Ac-PSMA-617 biochemical response evaluation criteria after treatment [any prostate specific antigen (PSA) decrease and PSA decrease >50% from baseline] to evaluate the treatment effect. Secondary endpoints included assessment of overall survival (OS), progression-free survival (PFS), molecular response, and toxicity for all studies. Two researchers conducted literature screening, data extraction and quality evaluation according to the inclusion and exclusion criteria. Use stata16.0 software for analysis, fixed-effects model for data merging and forest plots for display. RESULTS: A total of 6 retrospective studies, namely, 201 patients, were included in the final analysis. The pooled proportions of patients with decreased PSA and PSA decreased by more than 50% were 87.0% (95% confidence interval, 0.820 to 0.920) and 66.1% (95% confidence interval, 0.596 to 0.726), respectively. The pooled proportions of OS and PFS were 12.5 months (95%CI: 6.2-18.8 months) and 9.1 months (95%CI: 2.6-15.7 months). The patients showing molecular responses were 54% (95% confidence interval: 25-84%). In all studies, the most common side effect of 225Ac-PSMA-617 TAT was xerostomia, with any degree of xerostomia occurring in 77.1% (155 out of 201), and grade III only accounted for 3.0%. The second was 30.3% (61 out of 201) anemia of any degree, and grade III accounts for 7.5% (15 out of 201). Grade III leukopenia and thrombocytopenia were 4.5% (9 out of 201) and 5.5% (11 out of 201), respectively. Only 6 (3.0%) of 201 patients had Grade III nephrotoxicity. CONCLUSION: 225Ac-PSMA-617 is an effective and safe treatment option for mCRPC patients, and the toxicity caused by it is relatively low. However, future randomized controlled trials and prospective trials are required in the future to judge the therapeutic effects and survival benefits compared with existing clinical treatments. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42021281967.

Therapeutic efficacy of 225Ac-PSMA-617 targeted alpha therapy in patients of metastatic castrate resistant prostate cancer after taxane-based chemotherapy.

OBJECTIVES: 225Ac-PSMA-617 therapy has shown good response in many recent studies. We report our experience of targeted alpha therapy with 225Ac-PSMA-617 in mCRPC patients who have failed therapy with taxanes. MATERIALS AND METHODS: Thirty-eight patients with CRPC with progressive disease following at least one taxane-based chemotherapy received 225Ac-PSMA-617 between July 2017 and Nov 2019. Primary end point was a composite 50% PSA and radiological response. Secondary endpoints were PFS, OS, and changes in QOL. The differences in outcomes between patients with skeletal and lymph-node metastases versus those with visceral metastases were also studied. RESULTS: A composite response by predetermined criteria was observed in 25 (66%) of 38 patients. The median PFS was 8 months (95% CI 5.3-10.6 months). Median overall survival was 12 months (95% CI 9.1-14.9) with 16 patients alive at the time of censorship. There was no difference in response rates or survival statistics between patients with visceral metastases versus those with only bone and lymph-node metastases (Chi-square 1.51, df 1, Sig 0.218). The most common adverse effect was xerostomia. On the QOL Symptom score, Pain, Fatigue Insomnia, and constipation showed a significant improvement as compared to baseline. CONCLUSIONS: 225Ac-PSMA-617 is a safe and tolerable treatment option for mCRPC that demonstrates marked anti-tumour activity with improvement in quality of life even in patients of metastatic CRPC who have been previously treated with taxane-based chemotherapy.

Efficacy and safety of 225Ac-PSMA-617 targeted alpha therapy in metastatic castration-resistant Prostate Cancer patients.

Rationale: Despite the success of several standards of care treatment options in metastatic castration-resistant prostate cancer (mCRPC), a significant number of patients attain therapeutic resistance and eventually develop disease progression. Managing these patients are currently challenging. Hence, there is an unmet need for further efficient therapeutic options that induce anti-tumor activity and improve survival. The objective of this study was to assess the safety and therapeutic efficacy of 225Ac-PSMA-617 targeted alpha therapy (TAT) in mCRPC patients in real-world conditions. Methods: In this prospective study, we recruited patients with mCRPC who either were refractory to 177Lu-PSMA-617 radioligand therapy (RLT) or did not receive previous 177Lu-PSMA-617 RLT. Patients were treated with 225Ac-PSMA-617 TAT (100 KBq/Kg body weight) at 8-weekly intervals. The primary endpoint included the assessment of biochemical response by measuring the serum prostate-specific antigen (PSA) response rate as per the prostate cancer working group criteria (PCWG3). Secondary endpoints comprised the estimation of overall survival (OS), progression-free survival (PFS), molecular tumor response assessment (PERCIST 1 criteria), disease control rate (DCR), toxicity according to CTCAE v5.0, and clinical response evaluation. Results: A total of 28 patients were recruited for this cohort study among whom 15 (54%) received prior 177Lu-PSMA-617 RLT and the remaining 13 (46%) patients were 177Lu-PSMA-617 RLT naïve. The mean age was 69.7 years (range: 46-87 years). All patients, except one, had extensive skeletal metastases on baseline 68Ga-PSMA-11 PET/CT scan; one patient had lymph node dominant disease and advanced primary prostatic tumor. The mean activity administered was 26.5 ± 12 MBq (range: 9.25 - 62.9 MBq) [715.5 ± 327 µCi, range: 250 - 1700 µCi] with a median of 3 cycles (range: 1 - 7 cycles). At 8th week of post first cycle of 225Ac-PSMA-617 therapy (initial follow-up) and the end of the follow-up, >50% decline in PSA was observed in 25% and 39%, respectively. The median PFS and OS were 12 months (95% CI: 9 - 13 months) and 17 months (95% CI: 16 months - upper limit not reached), respectively. Molecular tumor response by PERCIST 1 criteria could be conducted in 22/28 (78.6%) patients, which revealed complete response in 2/22 (9%), partial response in 10/22 (45.4%) patients, 2/22 (9%) with stable disease, and 8/22 (36%) with progressive diseases. The disease control rate, according to the biochemical and molecular tumor response criteria, was 82% and 63.6%, respectively. Multivariate analysis revealed PSA progression as adverse prognostic indicator of OS, and any PSA decline as a good prognostic indicator of PFS. There was no Grade III/IV toxicity noted in this series. The most common side-effect was transient fatigue (50%) followed by grade I/II xerostomia (29%). Conclusion:225Ac-PSMA-617 TAT showed promising disease control rate, even when all other therapeutic options were exhausted, with low treatment-related toxicities.

68Ga-Prostate-specific membrane antigen (PSMA) positron emission tomography (pet) in prostate cancer: a systematic review and meta-analysis

ABSTRACT Introduction: Prostate cancer (PC) is the second most commonly diagnosed cancer in males. 68Ga-PSMA PET/CT, a non-invasive diagnostic tool to evaluate PC with prostate-specific membrane antigen (PSMA) expression, has emerged as a more accurate alternative to assess disease staging. We aimed to identify predictors of positive 68Ga-PSMA PET and the accuracy of this technique. Materials and methods: Diagnostic accuracy cross-sectional study with prospective and retrospective approaches. We performed a comprehensive literature search on PubMed, Cochrane Library, and Embase database in search of studies including PC patients submitted to radical prostatectomy or radiotherapy with curative intent and presented biochemical recurrence following ASTRO 1996 criteria. A total of 35 studies involving 3910 patients submitted to 68-Ga-PSMA PET were included and independently assessed by two authors: 8 studies on diagnosis, four on staging, and 23 studies on restaging purposes. The significance level was α=0.05. Results: pooled sensitivity and specificity were 0.90 (0.86-0.93) and 0.90 (0.82-0.96), respectively, for diagnostic purposes; as for staging, pooled sensitivity and specificity were 0.93 (0.86-0.98) and 0.96 (0.92-0.99), respectively. In the restaging scenario, pooled sensitivity and specificity were 0.76 (0.74-0.78) and 0.45 (0.27-0.58), respectively, considering the identification of prostate cancer in each described situation. We also obtained specificity and sensitivity results for PSA subdivisions. Conclusion: 68Ga-PSMA PET provides higher sensitivity and specificity than traditional imaging for prostate cancer.