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.

Long-Term Nephrotoxicity of 177Lu-PSMA Radioligand Therapy.

ß-emitting 177Lu targeting prostate-specific membrane antigen (PSMA) is an approved treatment option for metastatic castration-resistant prostate cancer. Data on its long-term nephrotoxicity are sparse. This study aimed to retrospectively evaluate post-177Lu-PSMA estimated glomerular filtration rate (eGFR) dynamics for at least 12 mo in a cohort of metastatic castration-resistant prostate cancer patients. Methods: The institutional databases of 3 German tertiary referral centers identified 106 patients who underwent at least 4 cycles of 177Lu-PSMA and had at least 12 mo of eGFR follow-up data. eGFR (by the Chronic Kidney Disease Epidemiology Collaboration formula) at 3, 6, and 12 mo after 177Lu-PSMA radioligand therapy was estimated using monoexponentially fitted curves through available eGFR data. eGFR changes were grouped (≥15%-<30%, moderate; ≥30%-<40%, severe; and ≥40%, very severe). Associations between eGFR changes (%) and nephrotoxic risk factors, prior treatment lines, and number of 177Lu-PSMA cycles were analyzed using multivariable linear regression. Results: At least moderate eGFR decreases were present in 45% (48/106) of patients; of those, nearly half (23/48) had a severe or very severe eGFR decrease. A higher number of risk factors at baseline (-4.51, P = 0.03) was associated with a greater eGFR decrease. Limitations of the study were the retrospective design, lack of a control group, and limited number of patients with a follow-up longer than 1 y. Conclusion: A considerable proportion of patients may experience moderate or severe decreases in eGFR 1 y from initiation of 177Lu-PSMA. A higher number of risk factors at baseline seems to aggravate loss of renal function. Further prospective trials are warranted to estimate the nephrotoxic potential of 177Lu-PSMA.

Comparative Analysis of Morphological and Functional Effects of 225Ac- and 177Lu-PSMA Radioligand Therapies (RLTs) on Salivary Glands.

Most Prostate Specific Membrane Antigens (PSMAs) targeting small molecules accumulate in the salivary glands (SGs), raising concerns about SG toxicity, especially after repeated therapies or therapy with 225Ac-labeled ligands. SG toxicity is assessed clinically by the severity of patient-reported xerostomia, but this parameter can be challenging to objectively quantify. Therefore, we explored the feasibility of using SG volume as a biomarker for toxicity. In 21 patients with late-stage metastatic resistant prostate cancer (mCRPC), the PSMA volume and ligand uptake of SG were analyzed retrospectively before and after two cycles of 177Lu-PSMA (LuPSMA; cohort A) and before and after one cycle of 225Ac-PSMA-617 (AcPSMA, cohort B). Mean Volume-SG in cohort A was 59 ± 13 vs. 54 ± 16 mL (-10%, p = 0.4), and in cohort B, it was 50 ± 13 vs. 40 ± 11 mL (-20%, p = 0.007), respectively. A statistically significant decrease in the activity concentration in the SG was only observed in group B (SUVmean: 9.2 ± 2.8 vs. 5.3 ± 1.8, p < 0.0001; vs. A: SUVmean: 11.2 ± 3.3 vs. 11.1 ± 3.5, p = 0.8). SG volume and PSMA-ligand uptake are promising markers to monitor the SG toxicity after a PSMA RLT.

Improved Quality of Life in Metastatic Castration-Resistant Prostate Cancer Patients Receiving Consecutive Cycles of 177Lu-PSMA I&T.

The aim of this retrospective analysis was to evaluate health-related quality of life (HRQoL) for patients with metastatic castration-resistant prostate cancer (mCRPC) receiving consecutive cycles of 177Lu-prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) using the reliable and validated European Organisation for Research and Treatment of Cancer core quality-of-life (QoL) questionnaire. In addition, differences in HRQoL between patients with early discontinuation of treatment because of disease progression and patients who were defined as eligible for treatment continuation were analyzed. Methods: In total, 60 mCRPC patients were included in this analysis. The European Organisation for Research and Treatment of Cancer core QoL questionnaire was completed at baseline, before each treatment cycle up to the sixth treatment cycle, and at the time of PSMA-ligand PET/CT scans after the second and fourth treatment cycles. QoL assessment included global health status, functional scales, and symptom burden during treatment. Results: Global health was significantly improved at the second and fourth cycles of 177Lu-PSMA RLT (P = 0.014 and P = 0.039, respectively). In line with this, role and emotional functioning showed significant improvements at the second and fourth treatment cycles (role functioning, P = 0.045 and P = 0.048, respectively, and emotional functioning, P = 0.035 and P = 0.007, respectively). In addition, compared with baseline, fatigue and pain were significantly alleviated at the second and fourth treatment cycles (pain, P = 0.035 and P = 0.034, respectively, and fatigue, P = 0.042 and P = 0.041, respectively). Other aspects of HRQoL, even if not significantly improved, remained stable over time, except for deterioration of fatigue at the study's end (P = 0.014) and reduction of dyspnea at the second treatment cycle (P = 0.012). Patients with early discontinuation of treatment showed a concordant decline in HRQoL. Conclusion: mCRPC patients showed significant improvement in HRQoL in the course of treatment with 177Lu-PSMA RLT. Furthermore, patients with early discontinuation of treatment showed an analogous decline in HRQoL.

Hsp70-A Universal Biomarker for Predicting Therapeutic Failure in Human Female Cancers and a Target for CTC Isolation in Advanced Cancers.

Heat shock protein 70 (Hsp70) is frequently overexpressed in many different tumor types. However, Hsp70 has also been shown to be selectively presented on the plasma membrane of tumor cells, but not normal cells, and this membrane form of Hsp70 (mHsp70) could be considered a universal tumor biomarker. Since viable, mHsp70-positive tumor cells actively release Hsp70 in lipid micro-vesicles, we investigated the utility of Hsp70 in circulation as a universal tumor biomarker and its potential as an early predictive marker of therapeutic failure. We have also evaluated mHsp70 as a target for the isolation and enumeration of circulating tumor cells (CTCs) in patients with different tumor entities. Circulating vesicular Hsp70 levels were measured in the peripheral blood of tumor patients with the compHsp70 ELISA. CTCs were isolated using cmHsp70.1 and EpCAM monoclonal antibody (mAb)-based bead approaches and characterized by immunohistochemistry using cytokeratin and CD45-specific antibodies. In two out of 35 patients exhibiting therapeutic failure two years after initial diagnosis of non-metastatic breast cancer, progressively increasing levels of circulating Hsp70 had already been observed during therapy, whereas levels in patients without subsequent recurrence remained unaltered. With regards to CTC isolation from patients with different tumors, an Hsp70 mAb-based selection system appears superior to an EpCAM mAb-based approach. Extracellular and mHsp70 can therefore serve as a predictive biomarker for therapeutic failure in early-stage tumors and as a target for the isolation of CTCs in various tumor diseases.

Enfortumab Vedotin in Metastatic Urothelial Carcinoma: Survival and Safety in a European Multicenter Real-world Patient Cohort.

Background: Treatment options for patients with urothelial cancer (UC) refractory to platinum and immunotherapy are limited and survival is short. Enfortumab vedotin (EV) is a monoclonal anti-NECTIN4 antibody conjugated to monomethyl auristatin. It was recently approved because of superior survival in comparison to standard-of-care (SOC) chemotherapy. Real-world patients, however, often have worse characteristics than patients included in clinical trials. Objective: To analyze the efficacy and safety of EV in a cohort of real-world patients. Design setting and participants: Retrospective data were collected from 23 hospitals and private practices for patients with metastatic and previously treated UC who received EV either when reimbursed by their insurance company before European Medicines Agency (EMA) approval, within a compassionate use program, or as SOC treatment after EMA approval. Imaging and therapy management were in accordance with local standards. Outcome measurements and statistical analysis: Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results and limitations: The median age for the 125 eligible patients was 66 yr (range 31-89). The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 for 76.0%, 2-4 for 13.6%, and unknown for 10.4% of patients. EV was administered in the fourth or later line for 44.8% of patients. The overall response rate was 41.6% (partial response 39.2%, complete response 2.4%). Median OS was 10.0 months (mo) (95% confidence interval 7.20-12.80) and median PFS was 5.0 mo (95% confidence interval 4.34-5.67). For patients with ECOG PS of 0-1, median OS was 14 mo. Any-grade AEs were observed in 67.2% and CTCAE grade ≥3 AEs in 30.4%. The most common AEs were peripheral sensory neuropathy and skin toxicity. Three fatal events (pneumonia, pneumonitis) occurred. Limitations include the retrospective design and short follow-up. Conclusions: Administration of EV for real-world patients was feasible with an acceptable toxicity profile. No new safety signals were reported. Antitumor activity in our cohort was comparable to data previously reported for trials. In summary, our results support the use of EV in patients with metastatic UC. Patient summary: Enfortumab vedotin is a medication that improved the survival of patients with bladder cancer in comparison to standard chemotherapy in clinical trials. However, patients included in clinical trials are highly selected and results for toxicities and improvements in survival do not always transfer to the real-world setting. We analyzed data for 125 patients who were treated with enfortumab vedotin. Our results are comparable to the outcomes from clinical trials regarding the safety and efficacy of this treatment.

The Impact of PSMA PET-Based Eligibility Criteria Used in the Prospective Phase II TheraP Trial in Metastatic Castration-Resistant Prostate Cancer Patients Undergoing Prostate-Specific Membrane Antigen-Targeted Radioligand Therapy.

Prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) has shown encouraging results for treatment of metastatic castration-resistant prostate cancer (mCRPC) in the prospective, multicenter, randomized phase II TheraP study. The inclusion criteria for that study comprised a pretherapeutic 68Ga-PSMA-11 PET scan showing sufficient tumor uptake using a predefined threshold and the absence of 18F-FDG-positive, PSMA ligand-negative tumor lesions. However, the prognostic value of these PET-based inclusion criteria remains unclear. Therefore, we evaluated the outcome of mCRPC patients treated with PSMA RLT using TheraP as well as other TheraP-based PET inclusion criteria. Methods: First, patients were dichotomized into 2 groups whose PSMA PET scans did (TheraP contrast-enhanced PSMA [cePSMA] PET-positive) or did not (TheraP cePSMA PET-negative) fulfill the inclusion criteria of TheraP. Notably, unlike in TheraP, 18F-FDG PET was not performed on our patients. Prostate-specific antigen (PSA) response (PSA decline ≥ 50% from baseline), PSA progression-free survival, and overall survival (OS) were compared. Additionally, patients were further dichotomized according to predefined SUVmax thresholds different from those used in TheraP to analyze their potential impact on outcome as well. Results: In total, 107 mCRPC patients were included in this analysis (TheraP cePSMA PET-positive, n = 77; TheraP cePSMA PET-negative, n = 30). PSA response rates were higher in TheraP cePSMA PET-positive patients than in TheraP cePSMA PET-negative patients (54.5% vs. 20%, respectively; P = 0.0012). The median PSA progression-free survival (P = 0.007) and OS (P = 0.0007) of patients were significantly longer in the TheraP cePSMA PET-positive group than in the TheraP cePSMA PET-negative group. Moreover, being in the TheraP cePSMA PET-positive group was identified as a significant prognosticator of longer OS (P = 0.003). The application of different SUVmax thresholds for a single hottest lesion demonstrated no influence on outcome in patients eligible for PSMA RLT. Conclusion: Patient selection for PSMA RLT according to the inclusion criteria of TheraP led to a better treatment response and outcome in our preselected patient cohort. However, a relevant number of patients not fulfilling these criteria also showed substantial rates of response.

[New tracers and combinations in radioligand therapy for prostate cancer]. / Neue Tracer und Kombinationen bei der Radioligandentherapie des Prostatakarzinoms.

BACKGROUND: 177Lutetium radioligand therapy directed against the prostate-specific membrane antigen (PSMA) is a new approved option for the treatment of metastatic, castration-resistant prostate cancer associated with a favorable toxicity profile. OBJECTIVES: What are new or emerging developments in radioligand therapy for prostate cancer? MATERIALS AND METHODS: A review of the current literature was performed. RESULTS: The further development of radioligand therapy for prostate cancer is currently taking place primarily in the following areas: application in earlier stages of the disease, use of alternative isotopes, development and use of new ligands, search for new target structures and combination with other forms of therapy. CONCLUSIONS: Radioligand therapy has become an integral part of the therapy algorithm in the treatment of metastatic, castration-resistant prostate cancer. Application in earlier stages of the disease is foreseeable. In the future, new ligands, alternative isotopes, new targets or combination therapies may increase efficacy and reduce toxicity.

Safety and Efficacy of [177Lu]-PSMA-I&T Radioligand Therapy in Octogenarians with Metastatic Castration-Resistant Prostate Cancer: Report on 80 Patients over the Age of 80 Years.

177Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new treatment option for metastatic castration-resistant prostate cancer (mCRPC). Its low toxicity profile favors use in elderly patients or in patients with critical comorbidities. The purpose of this analysis was to evaluate the efficacy and safety of [177Lu]-PSMA RLT in mCRPC patients at least 80 y old. Methods: Eighty mCRPC patients at least 80 y old underwent [177Lu]-PSMA-I&T RLT and were retrospectively selected. The patients were previously treated by androgen receptor-directed therapy, received taxane-based chemotherapy, or were chemotherapy-ineligible. The best prostate-specific antigen (PSA) response was calculated, as well as clinical progression-free survival (cPFS) and overall survival (OS). Toxicity data were acquired until 6 mo after the last treatment cycle. Results: Of 80 patients, 49 (61.3%) were chemotherapy-naïve and 16 (20%) had visceral metastases. The median number of previous mCRPC treatment regimens was 2. In total, 324 cycles (median, 4 cycles; range, 1-12) with a median cumulative activity of 23.8 GBq (interquartile range, 14.8-42.2) were applied. A PSA decline of 50% was achieved in 37 (46.3%) patients. Chemotherapy-naïve patients showed higher 50% PSA response rates than chemotherapy-pretreated patients (51.0% vs. 38.7%, respectively). Overall, median cPFS and OS were 8.7 and 16.1 mo, respectively. The median cPFS and OS of chemotherapy-naïve patients were significantly longer than those of chemotherapy-pretreated patients (10.5 vs. 6.5 mo and 20.7 vs. 11.8 mo, respectively, P < 0.05). A lower hemoglobin level and higher lactate dehydrogenase level at baseline were independent predictors of shorter cPFS and OS. Treatment-emergent grade 3 toxicities were anemia in 4 patients (5%), thrombocytopenia in 3 patients (3.8%), and renal impairment in 4 patients (5%). No nonhematologic grade 3 and no grade 4 toxicities were observed. The most frequent clinical side effects were grade 1-2 xerostomia, fatigue, and inappetence. Conclusion: [177Lu]-PSMA-I&T RLT in mCRPC patients at least 80 y old is safe and effective, comparable to previously published data on non-age-selected cohorts with a low rate of high-grade toxicities. Chemotherapy-naïve patients showed a better and longer response to therapy than taxane-pretreated patients. [177Lu]-PSMA RLT seems to be a meaningful treatment option for older patients.

Prognostic Role of 68Ga-PSMA11 PET-Based Response in Patients with Prostate Cancer Undergoing Taxane-Based Chemotherapy.

This study was performed to assess the prognostic utility of conventional biochemical and imaging response criteria and 68Ga-PSMA11 PET-adapted or -specific systems regarding overall survival (OS) in men with metastatic hormone-sensitive and castration-resistant prostate cancer (PC) treated with taxane-based chemotherapy. Methods: A total of 103 patients (metastatic hormone-sensitive PC, n = 57; castration-resistant PC, n = 46) underwent taxane-based chemotherapy. All patients had a minimum of 2 prostate-specific membrane antigen (PSMA) PET scans (at baseline and up to 3 mo after treatment). PSMA PET response was assessed by RECIST 1.1, adapted Prostate Cancer Working Group Criteria 3 (using PSMA PET instead of bone scan), aPERCIST, and PSMA PET progression (PPP) criteria. Response by each criterion was stratified by either progressive disease (PD) or non-PD. For aPERCIST, stratification by PD, stable disease (SD), and partial/complete remission (PR/CR) was performed. Biochemical response was determined by a prostate-specific antigen decrease of at least 50%. Subgroup analyses were performed by castration status. Univariable Cox proportional hazards regression analyses including Harrell's concordance indices were calculated to investigate the association of PD by response criteria and OS. Kaplan-Meier tests including log-rank statistics were calculated for survival analyses. Results: Twenty-six (25%) patients had unmeasurable disease by RECIST 1.1. PD by any response criterion was associated with an at least 2.5-fold increased risk of death and was highest for PD versus CR/PR by aPERCIST (hazard ratio, 11.4) on univariable regression. Stratified by castration status, a similar pattern was observed. PD by any criterion as associated with significantly shortened OS across overall and subgroup analyses. PR/CR by aPERCIST identified patients with lower risk of death and longer OS compared with patients with PD or SD. Conclusion: PSMA PET-based response criteria (PPP, aPERCIST, adapted Prostate Cancer Working Group Criteria 3) have high prognostic utility in men with metastatic PC undergoing taxane-based chemotherapy. PPP is simple to use, identified most patients with PD, and showed best prognostic utility regarding OS. PR/CR by aPERCIST identifies a subgroup of responders (PR/CR) showing better outcomes than patients with PD or SD. Future studies are warranted to amend the current paradigm relying on mere differentiation of PD versus non-PD in metastatic PC and to identify true treatment responders by imaging criteria.

Extensive 177Lu-PSMA Radioligand Therapy Can Lead to Radiation Nephropathy with a Renal Thrombotic Microangiopathy-like Picture.

Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA) radioligand therapy is an option that is increasingly being used for treatment of metastatic castration-resistant prostate cancer. This delivers ß-radiation to cells expressing PSMA and high accumulation of the radiopharmaceutical occurs in the kidneys. Here we report three cases of radiation nephropathy with severe chronic kidney disease induced by renal thrombotic microangiopathy following extensive treatment with 177Lu-PSMA radioligand therapy.

177Lu-PSMA-I&T for Treatment of Metastatic Castration-Resistant Prostate Cancer: Prognostic Value of Scintigraphic and Clinical Biomarkers.

The aim of this retrospective analysis was to determine prostate-specific antigen (PSA) response, PSA progression-free survival (PFS), and overall survival (OS) in a large cohort of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA-I&T and to identify clinical and scintigraphic prognostic factors for outcome. Methods: In total, 301 consecutive mCRPC patients were included in this analysis. Prognostic factors included clinical parameters, routine laboratory parameters, and findings on posttreatment scintigraphy. Scintigraphic tumor uptake of 177Lu-PSMA-I&T was compared with salivary gland uptake and classified as high or low. The longest extent of skeletal metastatic disease was measured, and its changes during therapy were used to define scintigraphic progression, response, and stable disease. A PSA response of at least 50%, PSA PFS, and OS were calculated. Results: In total, 1,138 cycles (median, 3 cycles per patient) of 177Lu-PSMA-I&T using a standard activity of 7.4 GBq were applied intravenously every 4-10 wk (median, 6 wk). Overall, 34% (95% CI, 28%-38%) of patients showed a PSA response of at least 50%, and the median PSA PFS and OS of the total patient cohort were 16.0 wk (95% CI, 12.1-19.9) and 13.8 mo (95% CI, 12.4-15.5), respectively. Patients with high scintigraphic tumor uptake showed a higher PSA response rate of at least 50% (45.7% vs. 10.4%; P < 0.0001) and a significantly reduced risk of PSA progression (median event time, 24.9 vs. 9.0 wk; hazard ratio, 0.3; 95% CI, 0.2-0.5; P < 0.0001). In our data, risk of death was not significantly different between patients with high scintigraphic uptake and those with low scintigraphic uptake (median, 14.4 vs. 12.4 mo; hazard ratio, 0.9; 95% CI, 0.6-1.3; P = 0.6). In a multivariable analysis, the following pretherapeutic prognostic factors for OS were identified: alkaline phosphatase, lactate dehydrogenase, and PSA levels; prior chemotherapy; and the presence of visceral metastases. Scintigraphic response was a strong prognostic factor for PSA response, PSA PFS, and OS after 1 treatment cycle. Conclusion: This retrospective analysis of a large group of consecutive patients corroborates previous clinical experience for 177Lu-PSMA-I&T in mCRPC and establishes previously proposed prognostic factors. The skeletal tumor extent and its changes were identified as new potential biomarkers to predict the outcome of therapy after the first treatment cycle.

Prospectively Accelerated T2-Weighted Imaging of the Prostate by Combining Compressed SENSE and Deep Learning in Patients with Histologically Proven Prostate Cancer.

BACKGROUND: To assess the performance of prospectively accelerated and deep learning (DL) reconstructed T2-weighted (T2w) imaging in volunteers and patients with histologically proven prostate cancer (PCa). METHODS: Prospectively undersampled T2w datasets were acquired with acceleration factors of 1.7 (reference), 3.4 and 4.8 in 10 healthy volunteers and 23 patients with histologically proven PCa. Image reconstructions using compressed SENSE (C-SENSE) and a combination of C-SENSE and DL-based artificial intelligence (C-SENSE AI) were analyzed. Qualitative image comparison was performed using a 6-point Likert scale (overall image quality, noise, motion artifacts, lesion detection, diagnostic certainty); the T2 and PI-RADS scores were compared between the two reconstructions. Additionally, quantitative image parameters were assessed (apparent SNR, apparent CNR, lesion size, line profiles). RESULTS: All C-SENSE AI-reconstructed images received a significantly higher qualitative rating compared to the C-SENSE standard images. Analysis of the quantitative parameters supported this finding, with significantly higher aSNR and aCNR. The line profiles demonstrated a significantly steeper signal change at the border of the prostatic lesion and the adjacent normal tissue in the C-SENSE AI-reconstructed images, whereas the T2 and PI-RADS scores as well as the lesion size did not differ. CONCLUSION: In this prospective study, we demonstrated the clinical feasibility of a novel C-SENSE AI reconstruction enabling a 58% acceleration in T2w imaging of the prostate while obtaining significantly better image quality.

Novel Framework for Treatment Response Evaluation Using PSMA PET/CT in Patients with Metastatic Castration-Resistant Prostate Cancer (RECIP 1.0): An International Multicenter Study.

Our objective was to develop version 1.0 of a novel framework for response evaluation criteria in prostate-specific membrane antigen (PSMA) PET/CT (RECIP) and a composite response classification that combines responses by prostate-specific antigen (PSA) measurements and by RECIP 1.0 (PSA + RECIP). Methods: This was an international multicenter, retrospective study. One hundred twenty-four men with metastatic castration-specific prostate cancer (mCRPC) who underwent 177Lu-PSMA therapy and received PSMA PET/CT at baseline and at an interim time point of 12 wk were included. Pairs of baseline interim PET/CT scans were interpreted by consensus among 3 masked readers for appearance of new lesions. Tumor lesions were segmented, and total PSMA-positive tumor volume (PSMA-VOL) was obtained. Appearance of new lesions and changes in PSMA-VOL were combined to develop RECIP 1.0, which included classifications of complete response (RECIP-CR: absence of any PSMA-ligand uptake on interim PET/CT), partial response (RECIP-PR: decline ≥ 30% in PSMA-VOL and no appearance of new lesions), progressive disease (RECIP-PD: increase ≥ 20% in PSMA-VOL and appearance of new lesions), and stable disease (RECIP-SD: any condition but RECIP-PR or RECIP-PD). Changes in PSA levels at 12 wk by Prostate Cancer Working Group Criteria 3 were recorded. PSA + RECIP results were defined as response (PSA decline ≥ 50% or RECIP-PR/CR) or progression (PSA increase ≥ 25% or RECIP-PD). The study's primary outcome measure was the prognostic value of RECIP 1.0 for overall survival (OS). The secondary outcome measure was the prognostic accuracy (C-index) of PSA + RECIP versus PSA responses. Results: Patients with RECIP-PD (n = 39; 8.3 mo) had a shorter OS than patients with stable disease (RECIP-SD) (n = 47; 13.1 mo; P < 0.001) or RECIP-PR (n = 38; 21.7 mo; P < 0.001). In identifying responders and progressors, PSA + RECIP had C-indices superior to those of PSA only: 0.65 versus 0.62 (P = 0.028) and 0.66 versus 0.63 (P = 0.044), respectively. Conclusion: PSMA PET/CT by RECIP 1.0 is prognostic for OS and can be used as a response biomarker to monitor early efficacy of 177Lu-PSMA in men with mCRPC. PSA + RECIP may be used as a novel composite endpoint in mCRPC clinical trial design.

[Update on systemic treatment of urothelial cancer: therapy in transition]. / Update Systemtherapie des Urothelkarzinoms ­ Therapie im Wandel.

The systemic treatment of locally advanced and metastatic urothelial carcinoma has been changing at a breathtaking pace for a few years. However, platinum-based chemotherapy continues to be the central component of perioperative therapies and first-line treatment in the metastatic stage. Immunotherapies with immune checkpoint inhibitors are now an integral part of therapy algorithms. New targeted forms of chemotherapy are about to be approved. Advances in understanding the molecular genetic analysis of tumour tissue will soon enable personalised therapy options. This article is intended to provide an overview of current systemic therapy options and the underlying database. New developments are identified by presenting ongoing phase III trials. After reading this article, the reader should feel informed about the current status of systemic therapy for urothelial carcinoma.

Cytoreductive radical prostatectomy after chemohormonal therapy in patients with primary metastatic prostate cancer.

OBJECTIVE: Cytoreductive radical prostatectomy (cRP) has been proposed as local treatment option in metastatic hormone-sensitive prostate cancer (mHSPC) to prevent local complications and potentially improve oncological outcomes. In this study, we examined the feasibility of a multimodal concept with primary chemohormonal therapy followed by cRP and analyzed prostate size reduction under systemic treatment, postoperative complication rates, as well as early postoperative continence. METHODS: In this retrospective study, 38 patients with mHSPC underwent cRP after primary chemohormonal therapy (3-monthly luteinising hormone-releasing hormone-analogue + six cycles 3-weekly docetaxel 75 mg/m2) at two centers between September 2015 and December 2018. RESULTS: Overall, 10 (26%) patients had high volume and 28 (74%) patients had low volume disease at diagnosis, according to CHAARTED definition. Median prostate-specific antigen (PSA) decreased from 65 ng/mL (interquartile range [IQR] 35.0-124.5 ng/mL) pre-chemotherapy to 1 ng/mL (IQR 0.3-1.7 ng/mL) post-chemotherapy. Prostate gland volume was significantly reduced by a median of 50% (IQR 29%-56%) under chemohormonal therapy (p = 0.003). Postoperative histopathology showed seminal vesicle invasion in 33 (87%) patients and negative surgical margins in 17 (45%) patients. Severe complications (Grade 3 according to Clavien-Dindo) were observed in 4 (11%) patients within 30 days. Continence was reached in 87% of patients after 1 month and in 92% of patients after 6 months. Median time to castration-resistance from begin of chemohormonal therapy was 41.1 months and from cRP was 35.9 months. Postoperative PSA-nadir ≤1 ng/mL versus >1 ng/mL was a significant predictor of time to castration-resistance after cRP (median not reached versus 5.3 months; p<0.0001). CONCLUSION: We observed a reduction of prostate volume under chemohormonal therapy going along with a low postoperative complication and high early continence rate. However, the oncologic benefit from cRP is still under evaluation.

Pretherapeutic Comparative Dosimetry of 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T in Patients with Metastatic Castration-Resistant Prostate Cancer.

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands allow for labeling with 18F and radiometals for endoradiotherapy. rhPSMA-7.3 has been designated as a lead compound with promising preclinical data for 177Lu-rhPSMA-7.3, which has shown higher tumor uptake than 177Lu-PSMA I&T. In this retrospective analysis, we compared pretherapeutic clinical dosimetry data of both PSMA ligands. Methods: Six patients with metastatic castration-resistant prostate cancer underwent both 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T pretherapeutic dosimetry. Whole-body scintigraphy was performed at 1 h, 4 h, 24 h, 48 h, and 7 d after injection. Regions of interest covering the whole body, organs, bone marrow, and tumor lesions were drawn for each patient. Absorbed doses for individual patients and pretherapeutic applications were calculated using OLINDA/EXM. To facilitate the comparison of both ligands, we introduced the therapeutic index (TI), defined as the ratio of mean pretherapeutic doses to tumor lesions over relevant organs at risk. Results: Mean whole-body pretherapeutic effective doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were 0.12 ± 0.07 and 0.05 ± 0.03 Sv/GBq, respectively. Mean absorbed organ doses for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T were, for example, 1.65 ± 0.28 and 0.73 ± 0.18 Gy/GBq for the kidneys, 0.19 ± 0.09 and 0.07 ± 0.03 Gy/GBq for the liver, 2.35 ± 0.78 and 0.80 ± 0.41 Gy/GBq for the parotid gland, and 0.67 ± 0.62 and 0.30 ± 0.27 Gy/GBq for the bone marrow, respectively. Tumor lesions received mean absorbed doses of 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T of 6.44 ± 6.44 and 2.64 ± 2.24 Gy/GBq, respectively. The mean TIs for the kidneys were 3.7 ± 2.2 and 3.6 ± 2.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively, and those for the bone marrow were 15.2 ± 10.2 and 15.1 ± 10.2 for 177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T, respectively. Conclusion: Pretherapeutic clinical dosimetry confirmed preclinical results of mean absorbed doses for tumors that were 2-3 times higher for 177Lu-rhPSMA-7.3 than for 177Lu-PSMA I&T. Absorbed doses to normal organs also tended to be higher for 177Lu-rhPSMA-7.3, resulting overall in similar average TIs for both radiopharmaceuticals with considerable interpatient variability. 177Lu-rhPSMA-7.3 has promise for a therapeutic efficacy similar to that of 177Lu-PSMA I&T at smaller amounts of injected activity, simplifying radiation safety measurements (especially for large patient numbers or dose escalation regimens).

Narrative review: prostate-specific membrane antigen-radioligand therapy in metastatic castration-resistant prostate cancer.

Radioactive-labelled ligands targeting the prostate-specific membrane antigen (PSMA), a transmembrane protein overexpressed in prostate cancer (PC), have shown promising activity in treatment of metastatic castration-resistant prostate cancer (mCRPC). PSMA-617 and PSMA-I&T (imaging and therapy), both labeled to the beta-emitter lutetium-177 (Lu177), are most frequently used in clinical routine and have shown a favorable side-effect profile. Common side effects are transient xerostomia. Severe side effects, e.g., treatment-associated myelosuppression, are rare. Currently treatment with Lu177-PSMA outside clinical trials is available for compassionate use for patients who exhausted conventional therapies. Previous retro- and prospective studies reported promising results with ≥50% PSA declines observed in at least one third of patients. Retrospective data suggests worse biochemical response in patients with visceral metastases. Preliminary data from the randomized phase II (TheraP) trial showed an improved biochemical response rate of Lu177-PSMA as compared to cabazitaxel in patients progressing after docetaxel. Following these promising data, the results of the randomized, prospective phase III VISION study are eagerly anticipated. A major challenge remains resistance to radioligand therapy with Lu177-PSMA. As an alternative, a PSMA-ligand labeled to the alpha-emitter Actinium-225 (Ac-225) may be offered to patients, which shows promising activity in patients developing progression under Lu177-PSMA at the cost of higher toxicity. Mostly permanent xerostomia is a relevant side effect resulting in treatment discontinuation in up to a quarter of patients. This review summarizes the literature on activity and toxicity of PSMA-targeted radioligand therapy in mCRPC.

Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study.

BACKGROUND: Lutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after 177Lu-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after 177Lu-PSMA in patients with mCRPC. METHODS: In this multicentre, retrospective study, we screened patients with mCRPC who had received 177Lu-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6·0-8·5 GBq 177Lu-PSMA once every 6-8 weeks, for a maximum of four to six cycles, and had available baseline [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [68Ga]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort. FINDINGS: Between April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [68Ga]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0·71 (95% CI 0·69-0·73). Similar C-indices were achieved at internal validation (0·71 [0·69-0·73]) and external validation (0·72 [0·68-0·76]). The C-index of the PSA-progression-free survival model was 0·70 (95% CI 0·68-0·72). Similar C-indices were achieved at internal validation (0·70 [0·68-0·72]) and external validation (0·71 [0·68-0·74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24·9 months [95% CI 16·8-27·3] vs 7·4 months [4·0-10·8]; p<0·0001) and PSA-progression-free survival (6·6 months [6·0-7·1] vs 2·5 months [1·2-3·8]; p=0·022). INTERPRETATION: These externally validated nomograms that are predictive of outcomes after 177Lu-PSMA in patients with mCRPC might help in clinical trial design and individual clinical decision making, particularly at institutions where 177Lu-PSMA is introduced as a novel therapeutic option. FUNDING: Prostate Cancer Foundation.

First Experience Using 18F-Flubrobenguane PET Imaging in Patients with Suspected Pheochromocytoma or Paraganglioma.

Pheochromocytomas and paragangliomas are a rare tumor entity originating from adrenomedullary chromaffin cells in the adrenal medulla or in sympathetic, paravertebral ganglia outside the medulla. Small lesions are especially difficult to detect by conventional CT or MRI and even by SPECT with the currently available radiotracers (e.g., metaiodobenzylguanidine [MIBG]). The novel PET radiotracer 18F-flubrobenguane could change the diagnostic paradigm in suspected pheochromocytomas and paragangliomas because of its homology with MIBG and the general advantages of PET imaging. The aim of this retrospective analysis was to evaluate 18F-flubrobenguane in pheochromocytomas and paragangliomas and to investigate the biodistribution in patients. Methods: Twenty-three patients with suspected pheochromocytoma or paraganglioma underwent PET/CT or PET/MRI at 63 ± 24 min after injection of 256 ± 33 MBq of 18F-flubrobenguane. The SUVmean and SUVmax of organs were measured with spheric volumes of interest. Threshold-segmented volumes of interest were used to measure the SUVmean or SUVmax of the tumor lesions. One reader evaluated all cross-sectional imaging datasets (CT or MRI) separately, as well as the PET hybrid datasets, and reported the lesion number and size. The diagnostic certainty for a positive lesion was scored on a 3-point scale. Results:18F-flubrobenguane showed a reproducible, stable biodistribution, with the highest SUVmax and SUVmean being in the thyroid gland (30.3 ± 2.2 and 22.5 ± 1.6, respectively), pancreas (12.2 ± 0.8 and 9.5 ± 0.7, respectively), and tumor lesions (16.8 ± 1.7 and 10.1 ± 1.1, respectively) and the lowest SUVmax and SUVmean being in muscle (1.1 ± 0.06 and 0.7 ± 0.04, respectively) and the lung (2.5 ± 0.17 and 1.85 ± 0.13, respectively). In a subgroup analysis, a significantly higher average SUVmean was seen for both pheochromocytoma and paraganglioma than for healthy adrenal glands (11.9 ± 2.0 vs. 9.9 ± 1.5 vs. 3.7 ± 0.2, respectively). In total, 47 lesions were detected. The reader reported more and smaller lesions with higher certainty in PET hybrid imaging than in conventional imaging; however, statistical significance was not reached. Of the 23 (23/47, 49%) lesions smaller than 1 cm, 61% (14/23) were found on hybrid imaging only. Conclusion: Our preliminary data suggest 18F-flubrobenguane PET to be a new, effective staging tool for patients with suspected pheochromocytoma or paraganglioma. Major advantages are the fast acquisition and high spatial resolution of PET imaging and the intense uptake in tumor lesions, facilitating detection. Further studies are warranted to define the role of 18F-flubrobenguane PET, particularly in comparison to standard diagnostic procedures such as MRI or 123I-MIBG SPECT/CT.