Microwave hyperthermia enhances radiosensitization by decreasing DNA repair efficiency and inducing oxidative stress in PC3 prostatic adenocarcinoma cells.

PURPOSE: Radiotherapy (RT) is the primary treatment for prostate cancer (PCa); however, the emergence of castration-resistant prostate cancer (CRPC) often leads to treatment failure and cancer-related deaths. In this study, we aimed to explore the use of microwave hyperthermia (MW-HT) to sensitize PCa to RT and investigate the underlying molecular mechanisms. METHODS: We developed a dedicated MW-HT heating setup, created an in vitro and in vivo MW-HT + RT treatment model for CRPC. We evaluated PC3 cell proliferation using CCK-8, colony experiments, DAPI staining, comet assay and ROS detection method. We also monitored nude mouse models of PCa during treatment, measured tumor weight, and calculated the tumor inhibition rate. Western blotting was used to detect DNA damage repair protein expression in PC3 cells and transplanted tumors. RESULTS: Compared to control, PC3 cell survival and clone formation rates decreased in RT + MW-HT group, demonstrating significant increase in apoptosis, ROS levels, and DNA damage. Lower tumor volumes and weights were observed in treatment groups. Ki-67 expression level was reduced in all treatment groups, with significant decrease in RT + MW-HT groups. The most significant apoptosis induction was confirmed in RT + MW-HT group by TUNEL staining. Protein expression levels of DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways significantly decreased in RT + MW-HT groups. CONCLUSION: MW-HT + RT treatment significantly inhibited DNA damage repair by downregulating DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways, leading to increased ROS levels, aggravate DNA damage, apoptosis, and necrosis in PC3 cells, a well-established model of CRPC.

[161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC: preliminary dosimetry results and intra-individual head-to-head comparison to [177Lu]Lu-PSMA-617.

Rationale: Evaluation of alternative radionuclides for use in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is currently focusing on 161Tb, which may provide advantages by emitting additional Auger and conversion electrons. In this pilot study, we present preliminary dosimetry data for [161Tb]Tb-PSMA-617 RLT in a direct comparison with [177Lu]Lu-PSMA-617. Method: Six patients with metastatic castration-resistant prostate cancer (mCRPC) underwent treatment with [177Lu]Lu-PSMA-617 and subsequently - after inadequate response - with [161Tb]Tb-PSMA-617. Whole-body planar and SPECT imaging-based dosimetry of organs at risk (kidneys and salivary glands) and tumor lesions were calculated using IDAC for 177Lu and OLINDA/EXM for 161Tb. The therapeutic index (TI) of mean tumor-absorbed doses over relevant organs at risk was calculated. Results: Mean absorbed doses to organs at risk of PSMA-RLT were slightly higher for [161Tb]Tb-PSMA-617 compared to [177Lu]Lu-PSMA-617 (kidneys: 0.643 ± 0.247 vs. 0.545 ± 0.231 Gy/GBq, factor 1.18; parotid gland: 0.367 ± 0.198 vs. 0.329 ± 0.180 Gy/GBq, factor 1.10), but markedly higher regarding tumor lesions (6.10 ± 6.59 vs 2.59 ± 3.30 Gy/GBq, factor 2.40, p < 0.001). Consequently, the mean TI was higher for [161Tb]Tb-PSMA-617 compared to [177Lu]Lu-PSMA-617 for both, the kidneys (11.54 ± 9.74 vs. 5.28 ± 5.13, p = 0.002) and the parotid gland (16.77 ± 13.10 vs. 12.51 ± 18.09, p = 0.008). Conclusion: In this intra-individual head-to-head pilot study, [161Tb]Tb-PSMA-617 delivered higher tumor-absorbed doses and resulted in superior TI compared to [177Lu]Lu-PSMA-617. This preliminary data support 161Tb as a promising radionuclide for PSMA-RLT in mCRPC.

Prognostic Performance of RECIP 1.0 Based on [18F]PSMA-1007 PET in Prostate Cancer Patients Treated with [177Lu]Lu-PSMA I&T.

In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on 68Ga- and 18F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean, SUVmax, PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 (P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression.

Single-Time-Point Renal Dosimetry Using Nonlinear Mixed-Effects Modeling and Population-Based Model Selection in [177Lu]Lu-PSMA-617 Therapy.

The aim of this study was to investigate the accuracy of single-time-point (STP) renal dosimetry imaging using SPECT/CT data, a nonlinear mixed-effects (NLME) model, and a population-based model selection (PBMS) in a large population for 177Lu-labeled prostate-specific membrane antigen therapy. Methods: Biokinetic data (mean ± SD) of [177Lu]Lu-PSMA-617 in kidneys at time points 1 (1.8 ± 0.8 h), 2 (18.7 ± 0.9 h), 3 (42.6 ± 1.0 h), 4 (66.3 ± 0.9 h), and 5 (160.3 ± 24.2 h) after injection were obtained from 63 patients with metastatic castration-resistant prostate cancer using SPECT/CT. Thirteen functions were derived from various parameterizations of 1- to 5-exponential functions. The function's parameters were fitted in the NLME framework to the all-time-point (ATP) data. The PBMS NLME method was performed using the goodness-of-fit test and Akaike weight to select the best function fitting the data. The best function from ATP fitting was used to calculate the reference time-integrated activity and absorbed doses. In STP dosimetry, the parameters of a particular patient with STP data were fitted simultaneously to the STP data at different time points of that patient with ATP data of all other patients. The parameters from STP fitting were used to calculate the STP time-integrated activity and absorbed doses. Relative deviations (RDs) and root-mean-square errors (RMSEs) were used to analyze the accuracy of the calculated STP absorbed dose compared with the reference absorbed dose obtained from the best-fit ATP function. The performance of STP dosimetry using PBMS NLME modeling was compared with the Hänscheid and Madsen methods. Results: The function [Formula: see text] was selected as the best-fit ATP function, with an Akaike weight of 100%. For STP dosimetry, the STP measurement by SPECT/CT at time point 3 (42.6 ± 1.0 h) showed a relatively low mean RD of -4.4% ± 9.4% and median RD of -0.7%. Time point 3 had the lowest RMSE value compared with those at the other 4 time points. The RMSEs of the absorbed dose RDs for time points 1-5 were 23%, 16%, 10%, 20%, and 53%, respectively. The STP dosimetry using the PBMS NLME method outperformed the Hänscheid and Madsen methods for all investigated time points. Conclusion: Our results show that a single measurement of SPECT/CT at 2 d after injection might be used to calculate accurate kidney-absorbed doses using the NLME method and PBMS.

The Impact of Baseline PSMA PET/CT Versus CT on Outcomes of 223Ra Therapy in Metastatic Castration-Resistant Prostate Cancer Patients.

Imaging before 223Ra-dichloride (223Ra) therapy is crucial for selecting metastatic castration-resistant prostate cancer (mCRPC) patients with bone-only disease. The purpose of this study was to evaluate if baseline prostate-specific membrane antigen (PSMA) PET/CT (bPSMA) versus CT is associated with outcomes of 223Ra therapy. Methods: A secondary analysis of the data of a prospective observational study (NCT04995614) was performed. Patients received a maximum of 6 223Ra cycles and were retrospectively divided into the bPSMA or baseline CT (bCT) groups. All patients received baseline bone scintigraphy. Primary endpoints were alkaline phosphatase and prostate-specific antigen response. Secondary endpoints were overall survival (OS) and radiologic response. Results: Between 2017 and 2020, 122 mCRPC patients were included: 18 (14.8%) in the bPSMA group and 104 (85.2%) in the bCT group. All baseline characteristics were comparable. No significant differences in alkaline phosphatase or prostate-specific antigen response were found. The bCT group showed an OS significantly shorter than that of the bPSMA group (12.4 vs. 19.9 mo, P = 0.038). In 31 of 76 patients (40.1%) in the bCT group who also received posttherapy CT, lymph node or visceral metastases (soft-tissue involvement [STI]) were detected after 223Ra therapy, compared with 0 of 15 patients in the bPSMA group who received posttherapy PSMA PET/CT or CT. No significant difference in OS was found between patients in the bCT or posttherapy CT subgroup without STI (46/76) and the bPSMA group. Conclusion: bPSMA versus CT does not seem to impact biochemical response during 223Ra therapy in mCRPC patients. Nevertheless, patients in the bCT group had a significantly shorter OS, most likely due to underdetection of STI in this group. Therefore, replacing bCT with PSMA PET/CT appears to be a valuable screening method for identifying patients who will benefit most from 223Ra therapy.

Dual 177 Lu-Prostate-Specific Membrane Antigen and 177 Lu-DOTATATE Therapy in Metastatic Castration-Resistant Prostate Cancer With Neuroendocrine Differentiation.

ABSTRACT: We present an 87-year-old man diagnosed with prostate cancer and neuroendocrine differentiation, posttherapy results to consecutive 177 Lu-prostate-specific membrane antigen and 177 Lu-DOTATATE. Despite hormonal therapy and chemoradiotherapy, the patient progressed rapidly, and multiple liver and bone metastases showed regression after 177 Lu-prostate-specific membrane antigen and 177 Lu-DOTATATE treatment. Prostate cancer with neuroendocrine differentiation is resistant to treatments; however, treatment with the combination of 177 Lu-DOTATATE therapy may be promising.

177Lu-PSMA therapy in metastatic prostate cancer: An updated review of prognostic and predictive biomarkers.

177Lu-PSMA has been approved for the treatment of PSMA-positive metastatic castration-resistant (mCRPC) patients who progressed to androgen receptor pathway inhibitors (ARPIs) and taxane-based chemotherapy. However, a higher proportion of patients do not respond to this type of radioligand therapy (RLT). To date, there is a lack of validated prognostic and predictive biomarkers for 177Lu-PSMA therapy in prostate cancer. Several studies have investigated the prognostic and predictive role of clinical and molecular factors and also the metabolic features of PET imaging. In this review, we aim to take stock of the current scenario, focusing on new emerging data from retrospective/prospective series and clinical trials. Given the high costs and the possibility of primary resistance, it seems essential to identify clinical and molecular characteristics that could allow clinicians to choose the right patient to treat with 177Lu-PSMA. Biomarker-based clinical trials are urgently needed in this field.

Quadruplet Therapy in De Novo High-Volume Mixed Neuroendocrine Prostate Cancer Using 177Lu-PSMA: A Case Report.

ABSTRACT: We present a case of de novo high-volume metastatic prostate cancer with high PSMA expression, partially PSMA-negative, using quadruplet therapy (PROMISE ver. 2 miTNM; miT4N2M1aM1b(dmi) PRIMARY score: 5, PSMA-expression score: 0-3). Because of our patient's partial PSMA negativity and after a multidisciplinary tumor board discussion, we decided to use a modified protocol involving doublet hormonal therapy along with 177Lu-PSMA and radiation therapy to address the PSMA-negative disease. The patient responded well to this treatment, but recurrence was ultimately inevitable. This case represents a typical example of mixed neuroendocrine prostate carcinoma and highlights its resistant phenotype in response to quadruplet therapy.

Circulating and Imaging Biomarkers of Radium-223 Response in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Radium-223 improves overall survival (OS) and reduces skeletal events in patients with bone metastatic castration-resistant prostate cancer (CRPC), but relevant biomarkers are lacking. We evaluated automated bone scan index (aBSI) and circulating tumor cell (CTC) analyses as potential biomarkers of prognosis and activity. PATIENTS AND METHODS: Patients with bone metastatic CRPC were enrolled on a prospective single-arm study of standard radium-223. 99mTc-MDP bone scan images at baseline, 2 months, and 6 months were quantitated using aBSI. CTCs at baseline, 1 month, and 2 months were enumerated and assessed for RNA expression of prostate cancer-specific genes using microfluidic enrichment followed by droplet digital polymerase chain reaction. RESULTS: The median OS was 21.3 months in 22 patients. Lower baseline aBSI and minimal change in aBSI (<+0.7) from baseline to 2 months were each associated with better OS (P = .00341 and P = .0139, respectively). The higher baseline CTC count of ≥5 CTC/7.5 mL was associated with worse OS (median, 10.1 v 32.9 months; P = .00568). CTCs declined at 2 months in four of 15 patients with detectable baseline CTCs. Among individual genes in CTCs, baseline expression of the splice variant AR-V7 was significantly associated with worse OS (hazard ratio, 5.20 [95% CI, 1.657 to 16.31]; P = .00195). Baseline detectable AR-V7, higher aBSI, and CTC count ≥5 CTC/7.5 mL continued to have a significant independent negative impact on OS after controlling for prostate-specific antigen or alkaline phosphatase. CONCLUSION: Quantitative bone scan assessment with aBSI and CTC analyses are prognostic markers in patients treated with radium-223. AR-V7 expression in CTCs is a particularly promising prognostic biomarker and warrants validation in larger cohorts.

Diffuse Pneumonitis after Lutetium-177-PSMA-617 Treatment in a Patient with Metastatic Castration-Resistant Prostate Cancer.

We present the case of a patient with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) who received lutetium Lu-177 vipivotide tetraxetan (also known as 177Lu-PSMA-617) due to progressive disease despite chemotherapy, hormonal therapy and radiation, including palliative mediastinal and central nervous system radiation. He was subsequently hospitalised for worsening acute onset dyspnoea despite clinically responding to therapy. Interval imaging revealed progressive multifocal ground-glass opacities superimposed on a background of underlying peribronchovascular fibrosis. Further workup, including an extensive workup to identify a possible infectious aetiology, ruled out most aetiologies leaving radiation pneumonitis (RP), radiation recall pneumonitis (RRP) and drug-induced pneumonitis as possible diagnoses secondary to 177Lu -PSMA-617. The associated imaging findings of ground-glass opacities and consolidation can be like other aetiologies such as acute infection and subsequently may be treated incorrectly. In the use of theragnostics like 177Lu -PSMA-617, it is fundamental to apply the practices of radioprotection learnt from radiotherapy, as well as to consider prior radiotherapy treatments and their possible side effects when used in conjunction.

Pretargeted radiotherapy and synergistic treatment of metastatic, castration-resistant prostate cancer using cross-linked, PSMA-targeted lipoic acid nanoparticles.

Metastatic castration-resistant prostate cancer (CRPC) is a currently incurable disease associated with high mortality. Novel therapeutic approaches for CRPC are urgently needed to improve prognosis. In this study, we developed cross-linked, PSMA-targeted lipoic acid nanoparticles (cPLANPs), which can interact with transmembrane glycoprotein to accumulate inside prostate cancer cells, where they upregulate caspase-3, downregulate anti-apoptotic B-cell lymphoma-2 (BCL-2), and thereby induce apoptosis. The trans-cyclooctene (TCO) decoration on cPLANPs acts as a bioorthogonal handle allowing pretargeted single-photon emission computed tomography and radiotherapy, which revealed significantly enhanced tumor accumulation and minimal off-target toxicity in our experiments. The developed strategy showed a strong synergistic anti-cancer effect in vivo, with a tumor inhibition rate of up to 95.6% after 14 days of treatment. Our results suggest the potential of combining bioorthogonal pretargeted radiotherapy with suitable PSMA-targeted nanoparticles for the treatment of metastatic CRPC.

Current Status of Prostate-specific Membrane Antigen-targeted Alpha Radioligand Therapy in Prostate Cancer.

Prostate cancer (PCa) is the most prevalent malignancy and leading cause of mortality in men. Despite the development of various drugs, such as novel androgen receptor signaling inhibitors and poly adenosine diphosphate-ribose polymerase inhibitors targeting homologous recombination repair-related genetic mutations, prognosis of metastatic castration-resistant prostate cancer remains unfavorable. However, recent advances in nuclear medicine have allowed for both imaging diagnostics and therapeutic interventions by targeting molecules specifically expressed in cancer cells with radioisotopes (RI). γ-rays are used in nuclear medicine imaging, whereas in therapy, α or ß-emitting RIs are administered to target cells in radiation therapy. PCa, in particular, exhibits the characteristic features of radioligand therapy, as the membrane protein prostate-specific membrane antigen (PSMA) is proportionally highly expressed in malignancy compared to normal tissues. The administered RI-labeled compound binds to PSMA, enabling specific targeting of PCa for treatment. Unlike ß-rays, α-rays have a shorter range and impart stronger energy to DNA, allowing α-particles to exhibit a higher linear energy transfer. Due to such characteristics, PSMA-targeted α radiotherapy is expected to have potent cytotoxic effects and fewer side effects on normal organs, making them more likely to be widely adopted in the future. However, reports on PSMA-targeted α radiotherapy differ in aspects, such as prior PSMA-targeted ß radiotherapy, the administered doses, and the number of treatment cycles. Therefore, in this review, we compile the reports on treatments utilizing α-emitting isotopes targeting PSMA in patients with PCa.

Metastatic castration resistant prostate cancer patients' experience with Radium-223 treatment in Japan.

Aim: We aimed to determine Japanese metastatic castration resistant prostate cancer (CRPC) patients' Ra-223 treatment experience. Patients & methods: Patients answered the Cancer Therapy Satisfaction Questionnaire (CTSQ domains: Satisfaction with Therapy [SWT], Expectations of Therapy [ET], Feelings about Side Effects [FSE]), the Memorial Anxiety Scale for Prostate Cancer (MAX-PC) and the FACT-Bone Pain (FACT-BP) Questionnaire at baseline, during (vists 3 and 5) and after treatment (end of observation; EOO). Results: Data from 72 patients were included. Baseline median CTSQ scores SWT: 66.1 (IQR19.7), ET: 75.0 (IQR45), and FSE 68.8 (IQR 34.4) were unchanged during vists 3 and 5, but the SWT (-3.57 [IQR17.9]) and ET (-5.0 [IQR30]) decreased while FSE was unchanged (0.0 [IQR31.25]) at EOO. The median MAX-PC (18.0 [IQR 49]) score was unchanged (0.0, IQR 6) while the median FACT BP (54.0 [IQR13]) score decreased by -1.0 (IQR 8) at EOO. Conclusion: Japanese metastatic castration resistant prostate cancer patients' experience is stable during Ra-223 treatment.

What is this study about? We wanted to know the treatment experience with Radium-223 (Ra-223) among Japanese prostate cancer patients. Ra-223 is a radioactive molecule used for the treatment of metastatic castration resistant prostate cancer. We asked patients to answer different questionnaires on treatment satisfaction, anxiety and quality of life before, during, and after treatment with Ra-223. What were the results? Based on the patients' answers to our questionnaires, treatment satisfaction, anxiety and quality of life remain stable while the patients undergo treatment with Ra-223, but in some aspects may decline after treatment. What do the results mean? The results mean that patients' experience during Ra-223 treatment is stable but patients should share any concerns they have about their treatment with their doctors.

Safety Analyses of the Phase 3 VISION Trial of [177Lu]Lu-PSMA-617 in Patients with Metastatic Castration-resistant Prostate Cancer.

BACKGROUND AND OBJECTIVE: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus the standard of care (SoC) significantly improved overall survival and radiographic progression-free survival versus SoC alone in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer in the VISION trial. We evaluated the safety of additional cycles of 177Lu-PSMA-617 and the impact of longer observation time for patients receiving 177Lu-PSMA-617 plus SoC. METHODS: VISION was an international, open-label study. Patients were randomised 2:1 to receive 177Lu-PSMA-617 plus SoC or SoC alone. The incidence of treatment-emergent adverse events (TEAEs) was assessed in prespecified subgroups of patients who received ≤4 cycles versus 5-6 cycles of treatment and during each cycle of treatment. The TEAE incidence was also adjusted for treatment exposure to calculate the incidence per 100 patient-treatment years of observation. This analysis was performed for the first occurrence of TEAEs. KEY FINDINGS AND LIMITATIONS: The any-grade TEAE incidence was similar in cycles 1-4 and cycles 5-6. TEAE frequency was similar across all cycles of 177Lu-PSMA-617 treatment. No additional safety concerns were reported for patients who received >4 cycles. The exposure-adjusted safety analysis revealed that the overall TEAE incidence was similar between arms, but distinct trends for different TEAE types were noted and the incidence of events associated with 177Lu-PSMA-617 remained higher in the 177Lu-PSMA-617 arm. CONCLUSIONS AND CLINICAL IMPLICATIONS: Longer exposure to 177Lu-PSMA-617 plus SoC was not associated with a higher toxicity risk, and the extended time for safety observation could account for the higher TEAE incidence in comparison to SoC alone. The findings support a favourable benefit-risk profile for 6 cycles of 177Lu-PSMA-617 in this setting and the use of up to 6 cycles of 177Lu-PSMA-617 in patients who are clinically benefiting from and tolerating this therapy. PATIENT SUMMARY: For patients with metastatic prostate cancer no longer responding to hormone therapy, an increase in the number of cycles of treatment with a radioactive compound called 177Lu-PSMA-617 from four to six had no additional adverse side effects.

177 Lu-PSMA-617 Therapy in a Case of Metastatic Castration-Resistant Prostate Cancer.

ABSTRACT: We report a 65-year-old man with metastatic castration-resistant prostate cancer who was treated with 2 cycles of 177 Lu-PSMA-617 therapy. PET/CT imaging of 68 Ga-PSMA-11 revealed a complete metabolic response (PERCIST1.0) after therapy. The prostate-specific antigen concentration drastically decreased (97.7% down).

Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study.

BACKGROUND: Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world. METHODS: This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (177Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival. FINDINGS: Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225Ac-PSMA RLT (median two cycles, IQR 2-4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6-519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0-17·5). The median overall survival was 15·5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225Ac-PSMA RLT. All patients who received more than seven cycles of 225Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded. INTERPRETATION: 225Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events. FUNDING: None.

Dosimetric Analysis of a Phase I Study of PSMA-Targeting Radiopharmaceutical Therapy With [177Lu]Ludotadipep in Patients With Metastatic Castration-Resistant Prostate Cancer.

OBJECTIVE: 177Lutetium [Lu] Ludotadipep is a novel prostate-specific membrane antigen targeting therapeutic agent with an albumin motif added to increase uptake in the tumors. We assessed the biodistribution and dosimetry of [177Lu]Ludotadipep in patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: Data from 25 patients (median age, 73 years; range, 60-90) with mCRPC from a phase I study with activity escalation design of single administration of [177Lu]Ludotadipep (1.85, 2.78, 3.70, 4.63, and 5.55 GBq) were assessed. Activity in the salivary glands, lungs, liver, kidneys, and spleen was estimated from whole-body scan and abdominal SPECT/CT images acquired at 2, 24, 48, 72, and 168 h after administration of [177Lu]Ludotadipep. Red marrow activity was calculated from blood samples obtained at 3, 10, 30, 60, and 180 min, and at 24, 48, and 72 h after administration. Organ- and tumor-based absorbed dose calculations were performed using IDAC-Dose 2.1. RESULTS: Absorbed dose coefficient (mean ± standard deviation) of normal organs was 1.17 ± 0.81 Gy/GBq for salivary glands, 0.05 ± 0.02 Gy/GBq for lungs, 0.14 ± 0.06 Gy/GBq for liver, 0.77 ± 0.28 Gy/GBq for kidneys, 0.12 ± 0.06 Gy/GBq for spleen, and 0.07 ± 0.02 Gy/GBq for red marrow. The absorbed dose coefficient of the tumors was 10.43 ± 7.77 Gy/GBq. CONCLUSION: [177Lu]Ludotadipep is expected to be safe at the dose of 3.7 GBq times 6 cycles planned for a phase II clinical trial with kidneys and bone marrow being the critical organs, and shows a high tumor absorbed dose.

Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591.

PURPOSE: Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225. METHODS: Following investigational new drug-enabling preclinical studies, we enrolled patients with progressive mCRPC that was refractory to or who refused standard treatment options (including androgen receptor pathway inhibitor and had received or been deemed ineligible for taxane chemotherapy). No selection for PSMA was performed. Patients received a single dose of 225Ac-J591 at one of seven dose-escalation levels followed by expansion at the highest dose. Primary end point of dose-escalation cohort was determination of dose-limiting toxicity (DLT) and RP2D. RESULTS: Radiochemistry and animal studies were favorable. Thirty-two patients received 225Ac-J591 in an accelerated dose-escalation design (22 in dose escalation, 10 in expansion). One patient (1 of 22; 4.5%) experienced DLT in cohort 6 (80 KBq/kg) but none in cohort 7; MTD was not reached, and RP2D was the highest dose level (93.3 KBq/kg). The majority of high-grade adverse events (AEs) were hematologic with an apparent relationship with administered radioactivity. Nonhematologic AEs were generally of low grade. Prostate-specific antigen (PSA) declines and circulating tumor cell (CTC) control were observed: 46.9% had at least 50% PSA decline at any time (34.4% confirmed PSA response), and protocol-defined CTC count response occurred in 13 of 22 (59.1%). CONCLUSION: To our knowledge, this is the first-in-human phase I dose-escalation trial of a single dose of 225Ac-J591 in 32 patients with pretreated progressive mCRPC demonstrated safety and preliminary efficacy signals. Further investigation is underway.