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BACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged life in patients with metastatic castration-resistant prostate cancer (mCRPC) in VISION (NCT03511664). However, distinguishing between patients likely and unlikely to respond remains a clinical challenge. We present the first multivariable models of outcomes with 177Lu-PSMA-617 built using data from VISION, a large prospective phase 3 clinical trial powered for overall survival. METHODS: Adults with progressive post androgen receptor pathway inhibitor and taxane prostate-specific membrane antigen (PSMA)-positive mCRPC received 177Lu-PSMA-617 plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, multivariable Cox proportional hazards models of overall survival (OS) and radiographic progression-free survival (rPFS), and a logistic regression model of prostate-specific antigen response (≥50% decline; PSA50) were constructed and evaluated using C-index or receiver operating characteristic (ROC) analyses with bootstrapping validation. Nomograms were constructed for visualisation. FINDINGS: Patients were randomised between June 2018 and October 2019. Data from all 551 patients in the 177Lu-PSMA-617 arm were analysed in multivariable modelling. The OS nomogram (C-index, 0.73; 95% confidence interval [CI], 0.70-0.76) included whole-body maximum standardised uptake value (SUVmax), time since diagnosis, opioid analgesic use, aspartate aminotransferase, haemoglobin, lymphocyte count, presence of PSMA-positive lesions in lymph nodes, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and neutrophil count. The rPFS nomogram (C-index, 0.68; 0.65-0.72) included SUVmax, time since diagnosis, opioid analgesic use, lymphocyte count, presence of liver metastases by computed tomography, LDH, and ALP. The PSA50 nomogram (area under ROC curve, 0.72; 95% CI, 0.68-0.77) included SUVmax, lymphocyte count and ALP. Performances of the OS and rPFS models were maintained when they were reconstructed excluding SUVmax. INTERPRETATION: These models of outcomes with 177Lu-PSMA-617 are the first built using prospective phase 3 data. They show that a combination of pretreatment laboratory, clinical, and imaging parameters, reflecting both patient and tumour status, influences outcomes. These models are important for aiding treatment selection, patient management, and clinical trial design. FUNDING: Novartis.

We report our initial real-world experience with 177Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177Lu-PSMA-617 radioligand therapy.

Background: The limited spatial resolution in SPECT images leads to partial volume effect (PVE), degrading the subsequent dosimetric accuracy. We aim to quantitatively evaluate PVE and partial volume corrections (PVC), i.e., recovery coefficient (RC)-PVC (RC-PVC), reblurred Van-Cittert (RVC) and iterative Yang (IY), in 177Lu-PSMA-617 SPECT images. Methods: We employed a geometrical cylindrical phantom containing five spheres (diameters ranging from 20 to 40 mm) and 40 XCAT phantoms with various anatomical variations and activity distributions. SIMIND Monte Carlo code was used to generate realistic noisy projections. In the clinical study, sequential quantitative SPECT/CT imaging at 4 time-points post 177Lu-PSMA-617 injections were analyzed for 10 patients. Iterative statistical reconstruction methods were used for reconstruction with attenuation, scatter and geometrical collimator detector response corrections, followed by post-filters. The RC-curves were fit based on the geometrical phantom study and applied for XCAT phantom and clinical study in RC-PVC. Matched and 0.5-2.0 voxels (2.54–10.16 mm) mismatched sphere masks were deployed in IY. The coefficient of variation (CoV) was measured on a uniform background on the geometrical phantom. RCs of spheres and mean absolute activity error (MAE) of kidneys and tumors were evaluated in simulation data, while the activity difference was evaluated in clinical data before and after PVC. Results: In the simulation study, the spheres experienced significant PVE, i.e., 0.26 RC and 0.70 RC for the 20 mm and 40 mm spheres, respectively. RVC and IY improved the RC of the 20 mm sphere to 0.37 and 0.75 and RC of the 40 mm sphere to 0.96 and 1.04. Mismatch in mask increased the activity error for all spheres in IY. RVC increased noise and caused Gibbs ringing artifacts. For XCAT phantoms, both RVC and IY performed comparably and were superior to RC-PVC in reducing the MAE of the kidneys. However, IY and RC-PVC outperformed RVC for tumors. The XCAT phantom study and clinical study showed a similar trend in the kidney and tumor activity differences between non-PVC and PVC. Conclusions: PVE greatly impacts activity quantification, especially for small objects. All PVC methods improve the quantification accuracy in 177Lu-PSMA SPECT. [ABSTRACT FROM AUTHOR]

Background: [177Lu]Lu–PSMA‐617 (177Lu‐PSMA‐617) plus protocol‐permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression‐free survival (rPFS) versus SOC in patients with prostate‐specific membrane antigen (PSMA)–positive metastatic castration‐resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health‐related quality of life (HRQOL). Methods: Post hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm (177Lu‐PSMA‐617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy–Prostate [FACT‐P] and 5‐level EQ‐5D [EQ‐5D‐5L]). Correlation analyses used an iterative multiple imputation copula‐based approach (correlation coefficients [rho] of <0.3 were defined as weak, ≥0.3 and <0.5 as mild, ≥0.5 and <0.7 as moderate, and ≥0.7 as strong). Results: In the overall population, rPFS correlated strongly with OS (rho, ≥0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT‐P total score and emotional and physical well‐being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time‐to‐worsening EQ‐5D‐5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms. Conclusions: In this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation. In patients with metastatic castration‐resistant prostate cancer participating in the VISION randomized phase 3 trial, radiographic progression‐free survival correlated strongly with overall survival but not with time to a first symptomatic skeletal event or worsening health‐related quality of life or pain. There were no clear or consistent differences in the strengths of correlation between the two treatment groups ([177Lu]Lu‐PSMA‐617 plus protocol‐permitted standard of care vs. standard of care alone). [ABSTRACT FROM AUTHOR]

Abstract Background The limited spatial resolution in SPECT images leads to partial volume effect (PVE), degrading the subsequent dosimetric accuracy. We aim to quantitatively evaluate PVE and partial volume corrections (PVC), i.e., recovery coefficient (RC)-PVC (RC-PVC), reblurred Van-Cittert (RVC) and iterative Yang (IY), in 177Lu-PSMA-617 SPECT images. Methods We employed a geometrical cylindrical phantom containing five spheres (diameters ranging from 20 to 40 mm) and 40 XCAT phantoms with various anatomical variations and activity distributions. SIMIND Monte Carlo code was used to generate realistic noisy projections. In the clinical study, sequential quantitative SPECT/CT imaging at 4 time-points post 177Lu-PSMA-617 injections were analyzed for 10 patients. Iterative statistical reconstruction methods were used for reconstruction with attenuation, scatter and geometrical collimator detector response corrections, followed by post-filters. The RC-curves were fit based on the geometrical phantom study and applied for XCAT phantom and clinical study in RC-PVC. Matched and 0.5-2.0 voxels (2.54–10.16 mm) mismatched sphere masks were deployed in IY. The coefficient of variation (CoV) was measured on a uniform background on the geometrical phantom. RCs of spheres and mean absolute activity error (MAE) of kidneys and tumors were evaluated in simulation data, while the activity difference was evaluated in clinical data before and after PVC. Results In the simulation study, the spheres experienced significant PVE, i.e., 0.26 RC and 0.70 RC for the 20 mm and 40 mm spheres, respectively. RVC and IY improved the RC of the 20 mm sphere to 0.37 and 0.75 and RC of the 40 mm sphere to 0.96 and 1.04. Mismatch in mask increased the activity error for all spheres in IY. RVC increased noise and caused Gibbs ringing artifacts. For XCAT phantoms, both RVC and IY performed comparably and were superior to RC-PVC in reducing the MAE of the kidneys. However, IY and RC-PVC outperformed RVC for tumors. The XCAT phantom study and clinical study showed a similar trend in the kidney and tumor activity differences between non-PVC and PVC. Conclusions PVE greatly impacts activity quantification, especially for small objects. All PVC methods improve the quantification accuracy in 177Lu-PSMA SPECT.

Summary: Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged life in patients with metastatic castration-resistant prostate cancer (mCRPC) in VISION (NCT03511664). However, distinguishing between patients likely and unlikely to respond remains a clinical challenge. We present the first multivariable models of outcomes with 177Lu-PSMA-617 built using data from VISION, a large prospective phase 3 clinical trial powered for overall survival. Methods: Adults with progressive post androgen receptor pathway inhibitor and taxane prostate-specific membrane antigen (PSMA)-positive mCRPC received 177Lu-PSMA-617 plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, multivariable Cox proportional hazards models of overall survival (OS) and radiographic progression-free survival (rPFS), and a logistic regression model of prostate-specific antigen response (≥50% decline; PSA50) were constructed and evaluated using C-index or receiver operating characteristic (ROC) analyses with bootstrapping validation. Nomograms were constructed for visualisation. Findings: Patients were randomised between June 2018 and October 2019. Data from all 551 patients in the 177Lu-PSMA-617 arm were analysed in multivariable modelling. The OS nomogram (C-index, 0.73; 95% confidence interval [CI], 0.70–0.76) included whole-body maximum standardised uptake value (SUVmax), time since diagnosis, opioid analgesic use, aspartate aminotransferase, haemoglobin, lymphocyte count, presence of PSMA-positive lesions in lymph nodes, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and neutrophil count. The rPFS nomogram (C-index, 0.68; 0.65–0.72) included SUVmax, time since diagnosis, opioid analgesic use, lymphocyte count, presence of liver metastases by computed tomography, LDH, and ALP. The PSA50 nomogram (area under ROC curve, 0.72; 95% CI, 0.68–0.77) included SUVmax, lymphocyte count and ALP. Performances of the OS and rPFS models were maintained when they were reconstructed excluding SUVmax. Interpretation: These models of outcomes with 177Lu-PSMA-617 are the first built using prospective phase 3 data. They show that a combination of pretreatment laboratory, clinical, and imaging parameters, reflecting both patient and tumour status, influences outcomes. These models are important for aiding treatment selection, patient management, and clinical trial design. Funding: Novartis.

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and a therapeutic target. Lutetium-177 (177Lu)-PSMA-617 is the first radioligand therapy to be approved in Canada for use in patients with metastatic castration-resistant prostate cancer (mCRPC). As this treatment represents a new therapeutic class, guidance regarding how to integrate it into clinical practice is needed. This article aims to review the evidence from prospective phase 2 and 3 clinical trials and meta-analyses of observational studies on the use of 177Lu-PSMA-617 in prostate cancer and discuss how Canadian clinicians might best apply these data in practice. The selection of appropriate patients, the practicalities of treatment administration, including necessary facilities for treatment procedures, the assessment of treatment response, and the management of adverse events are considered. Survival benefits were observed in clinical trials of 177Lu-PSMA-617 in patients with progressive, PSMA-positive mCRPC who were pretreated with androgen receptor pathway inhibitors and taxanes, as well as in taxane-naïve patients. However, the results of ongoing trials are awaited to clarify questions regarding the optimal sequencing of 177Lu-PSMA-617 with other therapies, as well as the implications of predictive biomarkers, personalized dosimetry, and combinations with other therapies.

We show that longer exposure to 177Lu-PSMA-617 treatment for up to six cycles was not associated with greater toxicity risk. Safety analyses support a favourable benefit-risk profile for six cycles of 177Lu-PSMA-617 in patients with progressive, prostate-specific membrane antigen–positive, metastatic castration-resistant prostate cancer. [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. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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 177Lu‐PSMA‐617 and 225Ac‐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. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and a therapeutic target. Lutetium-177 (177Lu)-PSMA-617 is the first radioligand therapy to be approved in Canada for use in patients with metastatic castration-resistant prostate cancer (mCRPC). As this treatment represents a new therapeutic class, guidance regarding how to integrate it into clinical practice is needed. This article aims to review the evidence from prospective phase 2 and 3 clinical trials and meta-analyses of observational studies on the use of 177Lu-PSMA-617 in prostate cancer and discuss how Canadian clinicians might best apply these data in practice. The selection of appropriate patients, the practicalities of treatment administration, including necessary facilities for treatment procedures, the assessment of treatment response, and the management of adverse events are considered. Survival benefits were observed in clinical trials of 177Lu-PSMA-617 in patients with progressive, PSMA-positive mCRPC who were pretreated with androgen receptor pathway inhibitors and taxanes, as well as in taxane-naïve patients. However, the results of ongoing trials are awaited to clarify questions regarding the optimal sequencing of 177Lu-PSMA-617 with other therapies, as well as the implications of predictive biomarkers, personalized dosimetry, and combinations with other therapies. [ABSTRACT FROM AUTHOR]

The human prostate–specific membrane antigen (PSMA) is substantially up-regulated in metastatic prostate cancer (PCa) cells. PSMA can be targeted by 177Lu conjugated to PSMA-617, a high-affinity ligand for the PSMA. The binding of the radioligand, 177Lu-PSMA-617, results in its internalisation and delivery of β-radiation into the cancer cells. However, PSMA-617, a component of the final product in the synthesis of the radioligand, may also play a role in the pathophysiology of PCa cells. The present study aimed to clarify the effects of PSMA-617 (10, 50 and 100 nM) on the expression of PSMA in PSMA-positive LNCaP cells, their proliferation, 177Lu-PSMA-617-induced cell death by WST-1 and lactate dehydrogenase assays, immunohistochemistry, western blotting, immunofluorescence staining and uptake of 177Lu-PSMA-617. PSMA-617 at 100 nM concentration induced cell-growth arrest, down-regulated cyclin D1 and cyclin E1 (by 43 and 36%, respectively) and up-regulated the cyclin-dependent kinase inhibitor p21Waf1/Cip1 (by 48%). Immunofluorescence staining demonstrated reduced content of DNA, pointing to a lower rate of cell division. PSMA-617 (up to 100 nM) did not alter the uptake of 177Lu-PSMA-617 into the LNCaP cells. Interestingly, simultaneous treatment with 177Lu-PSMA-617 and PSMA-617 for 24 and 48 h substantially potentiated the cell-death promoting effects of the radioligand. In conclusion, the combination of impeding tumour cell proliferation by PSMA-617 and its potentiation of the radiation-induced cell death brought about by 177Lu-PSMA-617 in PCa cells may considerably improve the outcome of the radiation therapy with 177Lu-PSMA-617, especially in patients with decreased radiosensitivity of PCa cells to the radioligand. [ABSTRACT FROM AUTHOR]

Simple Summary: Radioligand therapy (RLT) usually consists of predefined cycles of 177Lu-PSMA-617 every 6–8 weeks. Although side-effects of RLT are considered well tolerable, cumulative absorbed doses in kidneys and an increased probability of chronic renal failure in responders remain concerns. The aim of our retrospective study, therefore, was to assess the efficacy and safety of intermittent, response-adapted RLT with 177Lu-PSMA-617 in oligometastatic mCRPC patients. Intermittent RLT with 177Lu-PSMA-617 is effective and can result in long-lasting disease control in selected patients even when including multiple treatment-free periods. 177Lu-PSMA-617 radioligand therapy (177Lu-PSMA-RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC) currently consists of 4–6 cycles of 6.0–7.4 GBq of 177Lu-PSMA-617 each every 6–8 weeks. While safety and efficacy could be demonstrated in larger prospective trials irrespective of the tumor burden at 177Lu-PSMA RLT initiation, increased renal absorbed doses due to a reduced tumor sink effect in early responding, oligometastatic mCRPC patients pose difficulties. Response-adapted, dose distributing, intermittent treatment with up to six cycles has not been routinely performed, due to concerns about the potential loss of disease control. Treatment was discontinued in 19 early-responding patients with oligometastatic tumor burden after two (IQR 2–3) cycles of 177Lu-PSMA-RLT and 6.5 ± 0.7 GBq per cycle and resumed upon 68Ga-PSMA-11-PET/CT-based progression (according to the PCWG3 criteria). Subsequent treatment breaks were imposed if a PSMA-based imaging response could be achieved. A total of five (IQR 3–6) cycles reaching a cumulative activity of 32 ± 11 GBq were applied. A routine blood work-up including blood counts and liver and renal function was measured throughout the 177Lu-PSMA-RLT and follow-up to grade toxicity according to CTCAE v5.0 criteria. Survival outcome was calculated based on the Kaplan–Meier method. In total, treatment-free periods of 9 (IQR 6–17) cumulative months and the application of 177Lu-PSMA-RLT cycles over 16 (IQR 9–22) months could be achieved. Fifteen (84%) patients responded to subsequent cycles after the first treatment break and in 7/19 (37%) patients, intermittent 177Lu-PSMA-RLT consisted of ≥2 treatment breaks. The median PFS was 27 months (95% CI: 23–31) and overall survival was 45 months (95% CI: 28–62). No grade ≥3 hematological or renal toxicities could be observed during the 45 ± 21 months of follow-up. The cumulative mean renal absorbed dose was 16.7 ± 8.3 Gy and 0.53 ± 0.21 Gy/GBq. Intermittent radioligand therapy with 177Lu-PSMA-617 is feasible in early-responding patients with oligometastatic disease. A late onset of progression after subsequent cycles and the absence of significant toxicity warrants further investigation of the concept of intermittent treatment in selected patients. [ABSTRACT FROM AUTHOR]

The prostate-specific membrane antigen (PSMA) targeted radioligand therapy (PRLT) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients has generated significant interest among the oncologic community, with several publications documenting good response rates and survival benefits with low toxicity profiles. Indications, patient preparation, dose administration, post-treatment imaging, dosimetry, and side effect profiles of 177Lu-PSMA-617 are discussed in this article. We also discuss results from prospective studies, major retrospective studies, meta-analyses, clinical trials, and mentioned major ongoing clinical trials on PRLT. We have also portrayed our own experiences and future perspectives on PRLT. For PRLT, PSMA-617 and PSMA-I&T molecules have revolutionized the theranostic approach in the management of advanced prostate cancer, with solid backing from several published articles showing favorable outcomes and an excellent safety profile of 177Lu-PSMA-617. Improvement in quality of life and survival was seen in the majority of mCRPC patients after 177Lu-PSMA-617 PRLT. Patients with good performance status, asymptomatic, only lymph node metastases, high PSMA expressing lesions, and no discordant FDG avid lesions have a longer survival after 177Lu-PSMA-617 PRLT than patients with poor performance status, symptomatic, hepatic, brain, and skeletal metastases, discordant PSMA, and FDG-avid lesions. Docetaxel and cabazitaxel are approved treatments for mCRPC patients. 177Lu-PSMA-617 is approved as a third-line systemic treatment for mCRPC patients with failure to respond to androgen receptor pathway inhibitors and docetaxel therapy. PRLT is a safe and effective alternative to cabazitaxel (third-line systemic treatment), but it has a higher cost. 177Lu-PSMA-617 could be a more efficient therapeutic option for mCRPC patients as first-line or combined therapy, and it may be a useful therapeutic option for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) patients. Several clinical studies and clinical trials on PRLT are currently underway. In the future, the results of these trials will be helpful in evolving treatment strategies for prostate cancer patients. [ABSTRACT FROM AUTHOR]

Metastatic castrate resistant prostate cancer (mCPRC) remains an aggressive form of prostate cancer that no longer responds to traditional hormonal treatment alone. Despite the advent of novel anti-androgen medications, many patients continue to progress, and as a result, there is a growing need for additional treatment options. Lutetium-177 (177Lu) – PSMA-617 has become one of the new frontline treatment options for refractory metastatic castrate resistant prostate cancer after the failure of novel anti-androgen therapy and chemotherapy. Lu-177 has been used in real-world prospective trials and is now becoming utilized in newer phase III clinical trials. Here, we present a comprehensive overview of the current literature, covering retrospective studies, prospective studies, and clinical trials that established Lutetium-177-PSMA-617 (177Lu-PSMA-617) for the treatment of mCRPC. 177Lu – PSMA-617 has been approved for treatment of mCRPC based on positive phase III studies. While this treatment is tolerable and effective, biomarkers are necessary to determine which patients will benefit. In the future, radioligand treatments will likely be utilized in earlier lines of therapy and potentially in combination with other prostate cancer treatments. [ABSTRACT FROM AUTHOR]

Objective: Lutetium-177 prostate-specific membrane antigen-617 is a novel alternative therapeutic option in metastatic castration-resistant prostate cancer, especially useful for patients who do not respond to standard therapy methods. The aim of this study was to define the efficacy and safety profile of lutetium-177 prostate-specific membrane antigen-617 treatment in a group of patients with metastatic castration-resistant prostate cancer. Materials and Methods: Study group included 34 men with metastatic castration-resistant prostate cancer (median, 69.6 ± 7.7 years) who were treated with lutetium-177 prostate-specific membrane antigen-617 therapy (22/34; 4 courses, 12/34; 2 courses). Patients were evaluated by physical examination, Eastern cooperative oncology group performance status, gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography, brief pain inventory-short form questionnaire, biochemical tests, and complete blood counts. Treatment response and adverse effects were examined by brief pain inventory scores, SUVmax values, biochemical tests, and complete blood counts. Independent variables were analyzed statistically (significance; P < .05). Results: The Eastern cooperative oncology group performance was grade 0 in 5/34 (14.7%), grade 1 in 25/34 (73.5%), and grade 2 in 4/34 (11.8%) patients. Distribution of patient numbers according to brief pain inventory scores (score: <1, scores: 1-4, and scores: 5-10) was 2, 10 and 22 at the beginning, 6, 16 and 12 after the second course, and 10, 10 and 2 after the fourth course of treatment, respectively. Serum prostate-specific antigen decreased in 15 of 22 patients (68%) (P < .05). Before and after the treatment, we found a substantial decrease in SUVmax values (22.3 vs. 11.8, P < .001) and brief pain inventory scores (score = 5; 22/34 pts vs. 0/22 pts). The counts of white blood cells (P < .05), hemoglobin (P < .05), and thrombocytes (P = .001) were all significantly lower at the conclusion of the therapy. The most important adverse events were severe leukopenia (1/34 pts; 2.29 × 10 3/µL) and thrombocytopenia (3/34 pts; 32 000, 36 000, 32 000 106/L). Conclusion: We found that lutetium-177 prostate-specific membrane antigen-617 therapy is a promising treatment method for metastatic castration-resistant prostate cancer patients who are unresponsive to conventional therapy, according to our biochemical, positron emission tomography/computed tomography, and pain score outcomes. [ABSTRACT FROM AUTHOR]

Summary: This review summarizes current evidence of "theranostics" for patients with prostate cancer. Prostate-specific membrane antigen (PSMA) is a glycoprotein which can be labeled with positron-emitting tomographic (PET) tracers like fluorine-18, gallium-68, or copper-64 and can be labeled with beta emitters like lutetium-177 to treat patients with metastatic castration-resistant prostate cancer (mCRPC). PSMA PET/CT has been shown to be superior to computer tomography (CT) and bone scintigraphy in accuracy, sensitivity, and specificity in the evaluation of metastatic tumor sites and may change treatment management. However, outcome studies showing an improvement in progression-free survival (PFS) and/or overall survival (OS) after management change is missing. PSMA PET/CT is highly recommended in prostate cancer patients with biochemical recurrence (PSA > 0.2 ng/ml). Patients presenting with high PSMA expression in PSMA PET/CT may be favorably treated with 177lutetium-617. In the TheraP study, a multicenter phase 2 trial, patients with mCRPC were randomly assigned to receive either 177lutetium-617 or cabazitaxel. The results indicate fewer treatment-related adverse events in patients treated with 177lutetium-617, an improvement in PSA response, but no improvement in OS after 36 months follow-up. In the VISION trial, a phase 3 international study, patients with mCRPC were randomly assigned to receive either 177lutetium-617 and standard of care (SOC) or SOC alone. At 12 months, radiographic PFS or PSA-PFS was 18% in patients treated with 177lutetium-617 and 3% in patients treated with SOC alone. The real status of 177lutetium-617 in the sequel of treatment regimens remains unclear and additional studies are therefore warranted. [ABSTRACT FROM AUTHOR]

Abstract Background The recent phase III VISION-trial confirms the treatment efficacy of radioligand therapy with [177Lu]PSMA-617 (PSMA-RLT) in metastatic castration-resistant prostate cancer (mCRPC). In PSMA-RLT, the relatively low absorbed bone marrow dose allows for multiple therapy cycles with relatively low risk of haematological adverse events (hAE). However, as disease progression itself may be a cause of bone marrow impairment, the aim of this study was to assess potential relations between impairment of haematological status and response to PSMA-RLT. Methods In this retrospective analysis, haematological parameters (HP) of 64 patients with mCRPC were systematically acquired over two cycles (12–16 weeks) of PSMA-RLT from baseline to restaging. Changes in HP were analysed qualitatively (CTCAE 5.0) and quantitatively. The HP changes from baseline were compared to quantitative and qualitative biochemical and imaging response, using PCWG3 and PROMISE criteria. Results All grade 3/4 hAE observed were associated with disseminated or diffuse bone involvement as well as biochemical non-response at restaging. Quantitatively, at baseline, HP inversely correlated with biochemical and volumetric (on PET) tumour burden as well as bone involvement pattern (p ≤ 0.043). Among patients with disseminated or diffuse bone involvement, percentage changes in HP (%HP) at restaging inversely correlated with serological and imaging tumour burden (p ≤ 0.017). Biochemical non-responders showed a significant decrease in %HP (p ≤ 0.001) while HP in biochemical responders remained stable (p ≥ 0.079). Conclusion During early cycles of PSMA-RLT, qualitative and quantitative bone marrow impairment appears to be closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events, showing a significant decline of haematological parameters. This implies that in patients with advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles. German Clinical Trial Register DRKS00013665. Registered 28 December 2017, retrospectively registered ( www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013665 )

This study explored the gain value of fractionated administration of 177Lu-PSMA-617 in treating prostate cancer. 20% administration dosage of 177Lu-PSMA-617 realized 26.42% radiation accumulation of the normal dose, meanwhile, low-dose administration did not cause significant decrease in tumor PSMA expression within 3 days post injection. When compared with the conventional administration regimen, the fractionated administration regimen was of the same tumor inhibition rate, but showed more obvious tumor activity inhibition efficiency. Hence, the efficacy of PSMA-specific β-therapy can be improved via fractionated administration of radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

The treatment landscape for metastatic castration-resistant prostate cancer has evolved extremely in recent years and several drug classes are now available. Nonetheless, the lack of validated predictive biomarkers makes therapeutic choice and the best sequential approach difficult. The location of the metastatic site could be a valid criterion for choosing among the treatment options available. Although bone remains the most frequent metastatic site and a possible target for many drugs, recent data suggest a profound shift in the disease spectrum with visceral metastases increasing incidence. This review describes the presently available and ongoing therapies for patients with CRPC and bone metastases, focusing on the role of bone metastases as a possible driver for selecting therapies in these patients. [ABSTRACT FROM AUTHOR]

Background: [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) prolonged life in patients with metastatic castration-resistant prostate cancer (mCRPC) in VISION (NCT03511664). However, distinguishing between patients likely and unlikely to respond remains a clinical challenge. We present the first multivariable models of outcomes with 177 Lu-PSMA-617 built using data from VISION, a large prospective phase 3 clinical trial powered for overall survival., Methods: Adults with progressive post androgen receptor pathway inhibitor and taxane prostate-specific membrane antigen (PSMA)-positive mCRPC received 177 Lu-PSMA-617 plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, multivariable Cox proportional hazards models of overall survival (OS) and radiographic progression-free survival (rPFS), and a logistic regression model of prostate-specific antigen response (≥50% decline; PSA50) were constructed and evaluated using C-index or receiver operating characteristic (ROC) analyses with bootstrapping validation. Nomograms were constructed for visualisation., Findings: Patients were randomised between June 2018 and October 2019. Data from all 551 patients in the 177 Lu-PSMA-617 arm were analysed in multivariable modelling. The OS nomogram (C-index, 0.73; 95% confidence interval [CI], 0.70-0.76) included whole-body maximum standardised uptake value (SUV max ), time since diagnosis, opioid analgesic use, aspartate aminotransferase, haemoglobin, lymphocyte count, presence of PSMA-positive lesions in lymph nodes, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and neutrophil count. The rPFS nomogram (C-index, 0.68; 0.65-0.72) included SUV max , time since diagnosis, opioid analgesic use, lymphocyte count, presence of liver metastases by computed tomography, LDH, and ALP. The PSA50 nomogram (area under ROC curve, 0.72; 95% CI, 0.68-0.77) included SUV max , lymphocyte count and ALP. Performances of the OS and rPFS models were maintained when they were reconstructed excluding SUV max ., Interpretation: These models of outcomes with 177 Lu-PSMA-617 are the first built using prospective phase 3 data. They show that a combination of pretreatment laboratory, clinical, and imaging parameters, reflecting both patient and tumour status, influences outcomes. These models are important for aiding treatment selection, patient management, and clinical trial design., Funding: Novartis., Competing Interests: KH reports receiving grants or contracts from Boston Scientific, Janssen, and Novartis; consulting fees from Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, Isotopen Technologien München, Janssen, Merck, Molecular Partners, Novartis, NVision, POINT Biopharma, Pfizer, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, Sofie Biosciences, Telix, Theragnostics, and ymabs; and stock or other ownership in AdvanCell, Aktis Oncology, Convergent, NVision, Pharma 15, and Sofie Biosciences. JSdB reports receiving grants or contracts from Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Crescendo, Daiichi-Sankyo, Endocyte, Genentech/Roche, GlaxoSmithKline, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi Aventis; consulting or advisory fees from Astellas, AstraZeneca, Bayer, Daiichi-Sankyo, Genentech/Roche, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion, Pfizer, Sanofi Aventis, and Taiho; payment or honorarium from Astellas, AstraZeneca, Bayer, Cellcentric, Crecendo, Daiichi, Genentech, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Mycrix, MSD, Orion, Pfizer, Sanofi Aventis, and Taiho; being an inventor on patent 8,822,438; participating on a data safety monitoring or advisory board for Amgen, AstraZeneca, Bayer, Bioxcel Therapeutics, Crescendo, Daiichi-Sankyo, Endocyte, Genentech/Roche, GlaxoSmithKline, ImCheck Therapeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Oncternal, Pfizer, and Sanofi Aventis; and receiving institutional royalties or licenses related to abiraterone, PARP inhibitor, and PI3K/AKT. OS reports receiving support for the present manuscript from Novartis; institutional grants or contracts from Amgen, AstraZeneca, Bayer, Endocyte, Invitae, Janssen, Lantheus, Merck, Novartis, Progenics, and Tenebio; consulting fees from ARTBIO, AstraZeneca, Bayer, Blue Earth Diagnostics, Clarity Pharmaceuticals, Fusion, Isotopen Technologien Muenchen, Janssen, Merck, Myovant, Myriad, Noria Therapeutics, NorthStar, Novartis, Pfizer, POINT Biopharma, Sanofi, Telix, and Tenebio; travel and accommodation expenses from Lantheus, NorthStar, and Novartis; participation on a data safety monitoring or advisory board for AstraZeneca, Merck, and Pfizer; and stock or stock options in ARTBIO, Clarity Pharmaceuticals, Convergent, Fusion, Lilly, Pfizer, Ratio, and Telix. KNC reports receiving grants or contracts from AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, POINT Biopharma, and Roche; and consulting fees from Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis, Pfizer, POINT Biopharma, and Roche. BJK reports receiving consultant or advisory fees from Bayer, Isotope Technologies Munich, and Novartis; and research funding from Novartis. KR reports receiving consultant fees from ABX, ABX-CRO, Amgen, Bayer Healthcare, Janssen Cilag, Novartis, and Sirtex; and lecture payments from AstraZeneca, Bayer Healthcare, Novartis, and Siemens Healthcare. STT reports receiving institutional fees from AbbVie, Ambrx, Amgen, Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Clarity, Clovis, Endocyte, Genentech, Gilead, Inovio, Janssen, Karyopharm, Medivation, Merck, Newlink, Novartis, POINT Biopharma, Rexahn, Sanofi, and Seattle Genetics; and consultant fees from AbbVie, Aikido Pharma, Ambrx, Amgen, Astellas, Bayer, Blue Earth, Clarity Pharma, Clovis, Convergent Therapeutics, Daiichi Sankyo, Eisai, EMD Serono, Genentech, Genomic Health, Janssen, Medivation, Merck, Myovant, Novartis, Pfizer, POINT Biopharma, Regeneron, Sanofi, Seattle Genetics, Telix, Tolmar, and TransThera. JC reports stock or other ownership interest in Sofie Biosciences, Inc., and Trethera; acting as an uncompensated founder for Trethera; and an uncompensated adviser for Amgen, Atkis Oncology, Jubilant Radiopharma, Novartis, POINT Biopharma, and RayzeBio. GEH reports receiving consultant fees from Bayer HealthCare, Boston Scientific Corporation, NorthStar Medical Radioisotopes, Novartis, and Terumo; and stock ownership in Johnson and Johnson. CCW reports employment and stock ownership with Novartis. ZZ reports previous employment and current stock ownership with Novartis. CW reports employment and stock ownership with Novartis. OM reports employment and stock ownership with Novartis. MJM reports receiving consulting or advisory fees from Amgen, AstraZeneca, Blue Earth Diagnostics, Clarity Pharmaceuticals, Convergent Therapeutics, Daiichi, ITM Isotope Technologies Munich, Lantheus Medical Imaging, Pfizer, POINT Biopharma, Progenics, Telix Pharmaceuticals, and Z-Alpha; stock and other ownership in Doximity; travel, accommodations, and expenses from APCCC, AstraZeneca, and Memorial Sloan-Kettering Cancer Center; institutional research funding from Astellas Pharma, Bayer, Celgene, Corcept Therapeutics, Janssen, Novartis, Progenics, and Roche/Genentech; patents pending with Novartis; and royalties from Telix. KF reports receiving institutional honorarium or payments to Gustave Roussy Institute from Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, and Sanofi; institutional participation on data safety monitoring or advisory boards for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis, Pfizer, and Sanofi; and personal participation on a data safety monitoring or advisory board for Arvinas, CureVac, Macrogenics, Orion. No other potential conflict of interest relevant to this article was reported., (© 2024 The Authors.)

177 Lu can be imaged after administration using SPECT/CT. Most work to date has focused on using posttreatment imaging to measure normal organ and tumor dose. We aimed to assess the impact of posttreatment SPECT/CT on the management of patients undergoing 177 Lu-prostate-specific membrane antigen (PSMA) radiopharmaceutical therapy (RPT). Methods: In this retrospective study, 122 patients underwent PSMA RPT with subsequent SPECT/CT 24 h after treatment. We determined a qualitative response at each cycle and reviewed patient charts to assess the impact that posttreatment SPECT/CT had on patient management. Changes in patient management were classified as changes on the basis of progression and response, and specific cycles when they occurred were noted. Miscellaneous changes in patient management were also evaluated. Results: Among the 122 consecutive patients examined, 42%-56% exhibited stable disease, whereas 19%-39% of patients exhibited response on visual assessment across treatment cycles. In total, 49% ( n = 60) of patients experienced changes in management, of which 57% ( n = 34) were due to progression, 40% ( n = 24) were due to response, and 3% ( n = 2) were due to miscellaneous changes. Changes due to disease progression were observed mostly after cycles 2 and 4. Changes due to response to RPT occurred mostly after cycles 3 and 4. Conclusion: At our center, 49% of patients experienced changes in management based on posttreatment SPECT/CT, and most of these changes occurred at cycles 2 and 4. Integrating posttreatment SPECT/CT into routine PSMA RPT protocols can aid in patient management., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Treatment with 177 Lu-prostate-specific membrane antigen (PSMA)-617 ( 177 Lu-vipivotide tetraxetan [Pluvicto]) prolongs both progression-free and overall survival in advanced PSMA-positive metastatic castration-resistant prostate cancer. Data examining specifically neurologic symptoms after 177 Lu-PSMA-617 treatment are scarce. In this study, we aimed to review the neurologic findings in a large cohort of metastatic castration-resistant prostate cancer patients undergoing 177 Lu-PSMA-617 therapy. Methods: The clinical records and imaging data of patients who received their initial dose of 177 Lu-PSMA-617 between March 2022 and November 2022 were retrospectively reviewed. All patients presenting for medical evaluation, regardless of specific specialty appointments, with new or worsening neurologic symptoms were included in the study. Results: A total of 185 patients underwent 177 Lu-PSMA-617 therapy. The median age was 70 y (range, 58-90 y). The mean follow-up time was 12.04 ± 2.87 mo. Fifty-five new or worsening neurologic symptoms were observed in 50 patients (27%, 50/185). Of these, 27 (11.9%, 27/185) reported altered taste. Eleven patients (6%, 11/185) experienced dizziness with no other clear etiology; 2 of these patients were admitted to the emergency department (ED). Paresthesia symptoms were reported in 6 patients (3.2%, 6/185). Five patients (2.7%, 5/185) reported headaches, 3 of these patients were admitted to the ED because of the severity of the symptoms. Two patients (1.08%, 2/185) presented with extremity weakness. Two patients (1.08%, 2/185) had an ischemic stroke and were admitted to the ED. One patient (0.05%, 1/185) exhibited gait disturbances. In total, 7 patients (3.78%, 7/185) were admitted to the ED because of neurologic symptoms. None of the patients discontinued or failed to complete the 177 Lu-PSMA-617 therapy because of neurologic symptoms. Conclusion: After 177 Lu-PSMA-617 treatment, the most common neurologic symptoms were dysgeusia and dizziness. In this study, our follow-up period and population size might not have been sufficient to detect delayed or uncommon neurologic symptoms. In patients without neurologic symptoms or central nervous system metastases before treatment, we found the development of severe neurologic problems to be rare and unlikely to require discontinuation of treatment., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Abstract Background Myelosuppression is a potential dose-limiting factor in radioligand therapy (RLT). This study aims to investigate occurrence, severity and reversibility of hematotoxic adverse events in patients undergoing RLT with 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). The contribution of pretreatment risk factors and cumulative treatment activity is taken into account specifically. Methods RLT was performed in 140 patients receiving a total of 497 cycles. A mean activity of 6.9 $$\pm$$ ± 1.3 GBq 177Lu-PSMA-617 per cycle was administered, and mean cumulative activity was 24.6 $$\pm$$ ± 15.9 GBq. Hematological parameters were measured at baseline, prior to each treatment course, 2 to 4 weeks thereafter and throughout follow-up. Toxicity was graded based on Common Terminology Criteria for Adverse Events v5.0. Results Significant (grade ≥ 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade ≤ 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT. Myelosuppression was significantly more frequent in patients with pre-existing grade 2 cytopenia (OR: 3.50, 95%CI 1.08–11.32, p = 0.04) or high bone tumor burden (disseminated or diffuse based on PROMISE miTNM, OR: 5.08, 95%CI 1.08–23.86, p = 0.04). Previous taxane-based chemotherapy was associated with an increased incidence of significant hematotoxicity (OR: 4.62, 95%CI 1.23–17.28, p = 0.02), while treatment with 223Ra-dichloride, cumulative RLT treatment activity and activity per cycle were not significantly correlated (p = 0.93, 0.33, 0.29). Conclusion Hematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous 223Ra-dichloride treatment show no significant contribution to incidence rates.

Prostate specific membrane antigen (PSMA) is a transmembrane protein that is highly expressed on prostate epithelial cells and is strongly upregulated in prostate cancer. Radioligand therapy using beta-emitting Lutetium-177 (177Lu)-labeled-PSMA-617, a radiolabeled small molecule, has gained attention as a novel targeted therapy for metastatic prostate cancer, given its high affinity and long tumor retention, and rapid blood pool clearance. In March 2022, the United States Food and Drug administration has granted approval to the targeted 177Lu-PSMA-617 therapy for treatment of patients with PSMA-positive metastatic castration resistant prostate cancer, who have been previously treated with an androgen-receptor pathway inhibitor and taxane-based chemotherapy. Studies have demonstrated the adverse effects of this treatment, mainly encountered due to radiation exposure to non-target tissues. Salivary glands show high PSMA-ligand uptake and receive increased radiation dose secondary to accumulation of 177Lu-PSMA-617. This predisposes the glands to radiation-mediated toxicity. The exact mechanism, scope and severity of radiation-mediated salivary gland toxicity are not well understood, however, the strategies for its prevention and treatment are under evaluation. This review will focus on the current knowledge about salivary gland impairment post 177Lu labeled PSMA-based radioligand therapies, diagnostic methodologies, and imaging with emphasis on salivary gland scintigraphy. The preventive strategies and known treatment options would also be briefly highlighted.

Background: The recent phase III VISION-trial confirms the treatment efficacy of radioligand therapy with [177Lu]PSMA-617 (PSMA-RLT) in metastatic castration-resistant prostate cancer (mCRPC). In PSMA-RLT, the relatively low absorbed bone marrow dose allows for multiple therapy cycles with relatively low risk of haematological adverse events (hAE). However, as disease progression itself may be a cause of bone marrow impairment, the aim of this study was to assess potential relations between impairment of haematological status and response to PSMA-RLT. Methods: In this retrospective analysis, haematological parameters (HP) of 64 patients with mCRPC were systematically acquired over two cycles (12–16 weeks) of PSMA-RLT from baseline to restaging. Changes in HP were analysed qualitatively (CTCAE 5.0) and quantitatively. The HP changes from baseline were compared to quantitative and qualitative biochemical and imaging response, using PCWG3 and PROMISE criteria. Results: All grade 3/4 hAE observed were associated with disseminated or diffuse bone involvement as well as biochemical non-response at restaging. Quantitatively, at baseline, HP inversely correlated with biochemical and volumetric (on PET) tumour burden as well as bone involvement pattern (p ≤ 0.043). Among patients with disseminated or diffuse bone involvement, percentage changes in HP (%HP) at restaging inversely correlated with serological and imaging tumour burden (p ≤ 0.017). Biochemical non-responders showed a significant decrease in %HP (p ≤ 0.001) while HP in biochemical responders remained stable (p ≥ 0.079). Conclusion: During early cycles of PSMA-RLT, qualitative and quantitative bone marrow impairment appears to be closely associated with osseous tumour burden as only patients with advanced bone involvement and non-response to therapy exhibited high-grade haematological adverse events, showing a significant decline of haematological parameters. This implies that in patients with advanced mCRPC, non-response to PSMA-RLT may be a major cause of bone marrow impairment during early treatment cycles. German Clinical Trial Register DRKS00013665. Registered 28 December 2017, retrospectively registered (www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013665) [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is one of the most common malignancies affecting men, with poor prognosis after progression to metastatic castration-resistant prostate cancer (mCRPC). Radioligand therapy (RLT) targeting the overexpressed PSMA on PC cells, with, e.g., 177Lu-PSMA-617, has been effective in reducing tumor burden and prolonging survival in mCRPC. However, it is not a curative method with kidney and bone marrow toxicity limiting the activity given to patients. Previous preclinical models have reported transient hematotoxicity for up to 120 MBq. This activity may still be too low to investigate the effect on renal function since it corresponds to an absorbed dose below 10 Gy, whereas the kidneys in a clinical setting usually receive an absorbed dose more than double. Here we investigated the hematotoxicity and recovery after administered activities of 120, 160, and 200 MBq in a 177Lu-PSMA-617 BALB/cAnNRj mouse model. The animals had an initial drop in white blood cells (WBC) starting 4 days post injection, which recovered after 21 days. The effect on red blood cells (RBC) and platelets was detected later; 17 days post-injection levels decreased compared to the control group. The reduction was restored again 32 days post injection. No correlation between injected activity and hematotoxicity was found. Our results suggest that activities up to 200 MBq of 177Lu-PSMA-617 give transient hematotoxicity from which animals recover within a month and no radiation-related deaths. Injecting these high activities could allow animal studies with increased clinical relevance when studying renal toxicity in animal models. [ABSTRACT FROM AUTHOR]

Purpose: Lutetium-177 prostate-specific membrane antigen-617 (177Lu-PSMA-617) in end-stage metastatic castration-resistant prostate cancer (mCRPC) has reported favourable outcomes. In this study, we aimed to prospectively compare the efficacy and safety of 177Lu-PSMA-617 and docetaxel in chemotherapy-naïve mCRPC patients. Methods: This was a randomized, parallel-group, open-label, phase 2, and non-inferiority trial. Chemotherapy-naïve patients with mCRPC and high PSMA-expressing lesions on 68 Ga-PSMA-11 PET/CT were randomly assigned in 1:1 ratio to 177Lu-PSMA-617 (6.0–7.4 GBq/cycle, every 8 weeks, up to 4 cycles) or docetaxel (75 mg/m2/cycle, every 3 weeks, up to 10 cycles). The primary end-point was best prostate-specific antigen response rate (PSA-RR), defined according to Prostate Cancer Clinical Trials Working Group-3 as proportion of patients achieving ≥ 50% decline in PSA from baseline. Non-inferiority margin of − 15% was pre-specified for PSA-RR. Results: Between December 2019 and March 2021, 40 of the 45 patients assessed for eligibility underwent randomization. Fifteen of 20 patients in 177Lu-PSMA-617 arm and 20/20 patients in docetaxel arm received treatment per protocol. Of these, best PSA-RR in the 177Lu-PSMA-617 arm was 60% (9/15) versus 40% (8/20) in the docetaxel arm. The difference in the PSA-RRs between the two arms was 20% (95% confidence interval, CI: − 12–47, P = 0.25), meeting the pre-specified criterion for non-inferiority in per-protocol analysis. Further, progression-free survival rates at 6 months were 30% and 20% in the 177Lu-PSMA-617 and docetaxel arms respectively (difference 10%, 95% CI: − 18–38, P = 0.50). Overall, treatment-emergent grade ≥ 3 adverse events occurred less frequently with 177Lu-PSMA-617 than with docetaxel (6/20, 30% versus 10/20, 50%, respectively, P = 0.20). Quality-of-life outcomes improved significantly in 177Lu-PSMA-617 arm compared to docetaxel arm (P < 0.01). Conclusion: 177Lu-PSMA-617 was demonstrated to be safe and non-inferior to docetaxel in the treatment of mCRPC and could, thus, be potentially employed earlier in the disease course rather than being solely reserved for advanced end-stage disease. Clinical trial registration: Clinical Trials Registry-India, CTRI/2019/12/022282. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA) is a 100 kD, 750 amino acid (AA) long type II transmembrane glycoprotein that has a short N-terminal intracellular domain with 19 AA, 24 AA transmembrane proteins and a large C-terminal extracellular domain with 707 AA. PSMA has been mapped to chromosome 11p 11-12 in the region of the folate hydrolase gene (FOLH1) and has no known natural ligand. The protein possesses enzymatic activity—glutamate carboxypeptidase II (GCP-II)—and is thought to have role in folate uptake (FOLH1 gene). ‘PSMA’ expression, although significantly up-regulated in prostate carcinoma (more in high-risk and aggressive variants), is not exclusive for it and is noted in various other benign and malignant conditions, especially in the neovasculature. Currently, PSMA PET-CT is approved for high-risk and biochemically recurrent prostate carcinoma (PCa), and in patient selection for PSMA based theranostics. This review aims to highlight the clinical evolution of the PSMA molecule and PSMA PET-CT as a diagnostic modality, various indications of PSMA PET-CT, the appropriateness criteria for its use, pitfalls and artefacts, and other uses of PSMA PET apart from prostate carcinoma.

Despite the remarkable achievements in treating metastatic prostate cancer over the last two decades, castrate-resistant status is still considered the lethal stage of the disease. Theranostics combines a targeting compound (ligand) with a therapeutic radioisotope (radioactive particle) injected into the blood to target the cancer cells. The most studied radioligand is 177Lu-PSMA-617, which targets PSMA, a protein found in prostate cancer cells. This new approach has shown promising results in treating metastatic castration-resistant prostate cancer. Currently, many trials are using PSMA-targeting radioligands in combination with conventional therapies in advanced prostate cancer or even in the earlier stages of the disease. Other preclinical trials are exploring the possibility of using newer ligands or radioisotopes to treat prostate cancer to increase the specificity and efficacy of this treatment. [ABSTRACT FROM AUTHOR]

Background: Myelosuppression is a potential dose-limiting factor in radioligand therapy (RLT). This study aims to investigate occurrence, severity and reversibility of hematotoxic adverse events in patients undergoing RLT with 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). The contribution of pretreatment risk factors and cumulative treatment activity is taken into account specifically. Methods: RLT was performed in 140 patients receiving a total of 497 cycles. A mean activity of 6.9 ± 1.3 GBq 177Lu-PSMA-617 per cycle was administered, and mean cumulative activity was 24.6 ± 15.9 GBq. Hematological parameters were measured at baseline, prior to each treatment course, 2 to 4 weeks thereafter and throughout follow-up. Toxicity was graded based on Common Terminology Criteria for Adverse Events v5.0. Results: Significant (grade ≥ 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade ≤ 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT. Myelosuppression was significantly more frequent in patients with pre-existing grade 2 cytopenia (OR: 3.50, 95%CI 1.08–11.32, p = 0.04) or high bone tumor burden (disseminated or diffuse based on PROMISE miTNM, OR: 5.08, 95%CI 1.08–23.86, p = 0.04). Previous taxane-based chemotherapy was associated with an increased incidence of significant hematotoxicity (OR: 4.62, 95%CI 1.23–17.28, p = 0.02), while treatment with 223Ra-dichloride, cumulative RLT treatment activity and activity per cycle were not significantly correlated (p = 0.93, 0.33, 0.29). Conclusion: Hematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous 223Ra-dichloride treatment show no significant contribution to incidence rates. [ABSTRACT FROM AUTHOR]

The use of prostate-specific membrane antigen (PSMA)-based PET/CT has grown rapidly in recent years. This study estimated lesional uptake, normal physiologic concentrations, and temporal variation on delayed PET/CT of 68Ga-PSMA-11 across different molecular imaging PSMA (miPSMA) expression scores in patients with metastatic castration-resistant prostatic carcinoma. Methods: We retrospectively studied 50 patients who were evaluated for 177Lu-PSMA-targeted radioligand therapy and underwent 68Ga-PSMA-11 PET/CT to determine disease status. Their mean age was 67.5 ± 8 y (52-84 y), and their average serum prostate-specific antigen level was 401 ± 1,353 ng/mL (0.098-9,235.13 ng/mL) at the time of scanning. They underwent standard 68Ga-PSMA-11 PET/CT an average of 65 min after injection (60-90 min). Tumors (n = 50) were correlated with miPSMA expression score and uptake. Physiologic tracer distribution was estimated by placing a volume of interest 1 cm in diameter for smaller organs (submandibular, parotid, lacrimal, and tubarial glands; renal cortices; blood pool; and bowel) and 3 cm for larger organs (liver and spleen). SUVmax and SUVmean were estimated for each region. Tumor-to-spleen (T/S), tumor-to-liver (T/L), and tumor-to-parotid (T/P) ratios were calculated for each lesion. For 16 patients who underwent a delayed scan an average of 135 min after injection (120-150 min), additional analysis evaluated the effect of the delay. Results: Uptake was maximal in renal cortices, followed by salivary glands, bowel, spleen, liver, lacrimal glands, and blood pool. SUVmax averaged 37.7 ± 22.1 for renal cortices, 15.4 ± 7.3 for submandibular glands, 14.4 ± 7.1 for parotid glands, 9.4 ± 4.9 for spleen, 6.2 ± 3.7 for lacrimal glands, 5.9 ± 2.3 for liver, 5.3 ± 1.41 for tubarial glands, 13.8 ± 7.6 for bowel, and 2.4 ± 1.9 for blood pool. SUVmax averaged 10.33 ± 3.27 (6.46-17) for miPSMA expression score 2 and 38.21 ± 25.9 (7.68-119.08) for score 3. T/S and T/P ratios averaged 1.21 ± 0.44 (0.48-2.04) and 0.6 ± 0.18 (0.39-0.87), respectively, for score 2 and 5.05 ± 4.46 (1.25-20.89) and 3.15 ± 2.09 (1.06-9.45), respectively, for score 3. SUVmax for score 3 lesions averaged 18.85, which increased significantly to 26.24 on delayed imaging (P = 0.0001). However, T/L, T/S, and T/P ratios did not significantly change. Temporal variation in normal organs showed SUVmax to increase significantly on delayed scans for salivary (submandibular and parotid) and lacrimal glands and renal cortices, whereas SUVmean increased significantly for spleen; liver; and parotid, tubarial, and lacrimal glands and insignificantly for other organs. Conclusion: These data form a basis for a proposed consensus on standard reference ranges for quantitative 68Ga-PSMA-11 PET/CT. The temporal variations should be kept in mind for delayed acquisitions; T/S, T/L, and T/P ratios might serve as better markers for such scenarios. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect that external cooling of the salivary glands (ECSG) has on the uptake of gallium-68-labeled prostate-specific membrane antigen (68Ga-PSMA), as an indirect assessment of the capacity of ECSG to reduce the local dose in lutetium-177-PSMA-617 radioligand therapy. Materials and Methods: Ten patients with prostate cancer were submitted to 68Ga-PSMA positron emission tomography/computed tomography with unilateral ECSG. The ECSG was started at 30 min before the injection of the radiotracer and maintained until the end of image acquisition (1 h after injection). Each salivary gland was assessed by determining the maximum, mean, and peak standardized uptake values (SUVmax, SUVmean, and SUVpeak, respectively). The volume of each gland was determined in a volume of interest delineated by a threshold SUVmax of 10%. Paired Student's t-tests were used in order to compare the results. Results: In terms of the SUV parameters, there were no statistically significant differences between the cooled and contralateral salivary glands. However, the mean volume was 27% lower in the cooled parotid glands than in the contralateral parotid glands (p = 0.004). Conclusion: The use of ECSG does not appear to reduce 68Ga-PSMA uptake by the salivary glands. In addition, there is yet no evidence that ECSG is effective in preventing salivary gland toxicity. [ABSTRACT FROM AUTHOR]

Aim: The objective of this study was to estimate the absorbed doses to the normal organs and tumor lesions in metastatic castration-resistant prostate cancer (mCRPC) patients treated with indigenously developed 177Lu-PSMA-617 that could establish optimal treatment protocol with minimum risk to the dose-limiting organs. Furthermore, attempt was also made to compare radiation absorbed doses for normal organs and tumor lesions in subsequent cycles of 177Lu-PSMA-617 peptide receptor radioligand therapy (PRLT) in the same group of patients during the course of treatment. Methods: A total of 30 patients of proven mCRPC were enrolled for this prospective study. These patients received up to 5 cycles of treatment with 177Lu-PSMA-617 PRLT (1 cycle for 13 patients, 2 cycles for 9 patients, 3 cycles for 3 patients, and 5 cycles for 5 patients), at 11-12-week intervals between the two successive therapies. The patients underwent postadministration whole-body scintigraphy at five time points: 0.5 (prevoid), 2, 12, 24, and 72/96 h (postvoid). From time-activity curves generated by drawing regions of interests on the images, number of disintegrations was determined. Tumor masses were estimated from pretherapeutic 68Ga-PSMA-11 positron emission tomography-computed tomography images. Absorbed doses for organs and tumors were calculated using OLINDA 2.0 software. Results: The average activity of 177Lu-PSMA-617 (mean ± SD) administered per patient per cycle was 4.94 ± 0.45 GBq. The mean absorbed organ doses (mean ± SD) from first therapy cycle in Gy/GBq were as follows: kidneys 0.52 ± 0.16, spleen 0.17 ± 0.07, liver 0.08 ± 0.05, salivary glands 0.53 ± 0.30, lacrimal glands 1.45 ± 0.85, nasal mucosa membrane 0.46 ± 0.19, urinary bladder 0.23 ± 0.02, and bone marrow 0.04 ± 0.03. The mean effective dose for whole body from first therapy cycle was 0.05 ± 0.03 Sv/GBq. Among all the normal organs, lacrimal glands received the highest absorbed dose. The median dose for all lesions, bone lesions, lymph nodes, primary site, liver lesion, lung lesion, and soft tissue deposit from first therapy cycle was determined to be 4.17, 4.23, 3.96, 4.36, 10.27, 0.78, and 4.68 Gy/GBq respectively. Absorbed doses received by the normal organs in five consecutive cycles follow three different trends, (a) for kidneys, salivary glands, and nasal mucous membrane, absorbed doses increased from first therapy cycle to second therapy cycle and then slowly decreased in subsequently therapy cycles; (b) for spleen, liver, and lacrimal glands, absorbed doses decreased with the successive therapy cycles; and (c) in case of bone marrow, bladder, and whole body, mean absorbed dose almost remained constant in each therapy cycle. Absorbed doses to the lesions gradually decreased with increase of the number of therapy cycles. Conclusions: The organ and tumor absorbed doses of 177Lu-PSMA-617 in mCRPC patients were found to be comparable to the data reported in the literature. The highest absorbed organ dose was observed in lacrimal glands and being a dose limiting organ, a cumulative activity up to 32.5 GBq (878 mCi) of 177Lu-PSMA-617 in 4-5 therapy cycles appears safe and feasible to achieve full therapeutic window. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is one of the most common malignancies affecting men, with poor prognosis after progression to metastatic castration-resistant prostate cancer (mCRPC). Radioligand therapy (RLT) targeting the overexpressed PSMA on PC cells, with, e.g., 177Lu-PSMA-617, has been effective in reducing tumor burden and prolonging survival in mCRPC. However, it is not a curative method with kidney and bone marrow toxicity limiting the activity given to patients. Previous preclinical models have reported transient hematotoxicity for up to 120 MBq. This activity may still be too low to investigate the effect on renal function since it corresponds to an absorbed dose below 10 Gy, whereas the kidneys in a clinical setting usually receive an absorbed dose more than double. Here we investigated the hematotoxicity and recovery after administered activities of 120, 160, and 200 MBq in a 177Lu-PSMA-617 BALB/cAnNRj mouse model. The animals had an initial drop in white blood cells (WBC) starting 4 days post injection, which recovered after 21 days. The effect on red blood cells (RBC) and platelets was detected later; 17 days post-injection levels decreased compared to the control group. The reduction was restored again 32 days post injection. No correlation between injected activity and hematotoxicity was found. Our results suggest that activities up to 200 MBq of 177Lu-PSMA-617 give transient hematotoxicity from which animals recover within a month and no radiation-related deaths. Injecting these high activities could allow animal studies with increased clinical relevance when studying renal toxicity in animal models.

We report our initial real-world experience with 177 Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177 Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177 Lu-PSMA-617 radioligand therapy., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Radioligand therapy with [177Lu]Lu-PSMA-617 is efficacious for the treatment of patients with metastasized castration-resistant prostate cancer (mCRPC). Various studies have evaluated the efficacy and safety of [177Lu]Lu-PSMA-617 using a dose of 6.0 GBq and an 8-week therapy interval. However, the first prospective phase III trial (VISION) plans to use an elevated cumulative dose by applying 7.5 GBq in a 6-week interval. The aim of the present study was to compare safety and efficacy of the two aforementioned [177Lu]Lu-PSMA-617 therapy regimes (7.5 GBq every 6 weeks vs. 6.0 GBq every 8 weeks). Methods: A total number of 78 consecutive patients with mCRPC and a history of first-line chemotherapy were included in this retrospective analysis. The outcome of patients treated with 6.0 GBq [177Lu]Lu-PSMA-617 per cycle (n = 37) were compared with those treated with 7.5 GBq (n = 41) per cycle. The median therapy intervals were 8.4 weeks (6.0 GBq group) vs. 6.5 (7.5 GBq group). PSA response, PSA progression-free survival (PSA-PFS), overall survival, and adverse events were evaluated and compared between both groups. Chi-squared test, Kaplan Meier estimates, Cox regression, and log-rank test were used. The highest decline from pretherapeutic PSA levels was measured as percentage (best PSA response) and compared between groups by Wilcoxon test. Results: There was no significant difference comparing the rate of > 50% PSA decline or best PSA response between the 6.0 GBq and 7.5 GBq group (35% vs. 54%, p = 0.065; and − 40.2% vs. − 57.8%, p = 0.329). The median estimated survival and PSA-PFS did not significantly differ between the 6.0 GBq and 7.5 GBq groups as well (11.3 vs. 12.7 months, p = 0.384; and 9.5 vs. 12.3 months, p = 0.258). There was no significant difference regarding the change of kidney, liver, and blood cell parameters under therapy between the treatment groups. Conclusion: Higher cumulated doses of [177Lu]Lu-PSMA-617 were well tolerated and caused no significantly increased rate of adverse reactions. Moreover, 7.5 GBq of [177Lu]Lu-PSMA-617 every 6 weeks causes slightly higher, though not statistically significant, response rates and seems therefore to be the preferable treatment regime. However, future studies are needed to elucidate the dose-related efficacy of [177Lu]Lu-PSMA-617 as a way to personalized medicine. [ABSTRACT FROM AUTHOR]

Introduction: A new therapeutic option for metastatic castration–resistant prostate cancer (mCRPC) of heavily pre-treated patients lies in 177Lu-PSMA-617 radioligand therapy. Methods: On the basis of PSMA-targeted 68Ga-PSMA-11 PET/CT, 32 consecutive mCRPC patients were selected for 177Lu-PSMA-617 therapy (6 GBq/cycle, 2 to 6 cycles, 6–10 weeks apart) and followed until death. Post-therapy whole-body (WB) dosimetry and 68Ga-PSMA-11 PET/CT data were compared and related to progression free and overall survival. Results: 177Lu-PSMA-617 dosimetry after the first cycle indicated high tumor doses for skeletal (4.01 ± 2.64; range 1.10–13.00 Gy/GBq), lymph node (3.12 ± 2.07; range 0.70–8.70 Gy/GBq), and liver (2.97 ± 1.38; range 0.76–5.00 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 24 GBq. Any PSA decrease after the first cycle was found in 23/32 (72%), after the second cycle in 22/32 (69%), after the third cycle in 16/28 (57%), and after the fourth cycle in 8/18 (44%) patients. Post-therapy 24 h WB scintigraphy showed decreased tumor-to-background ratios in 24/32 (75%) after the first therapy cycle, after the second cycle in 17/29 (59%), and after the third cycle in 13/21 (62%) patients. The median PFS was 7 months and the median OS 12 months. In the group of PSA responders (n = 22) the median OS was 17 months versus 11 months in the group of non-responders (n = 10), p < 0.05. Decreasing SUVmax values were found for parotid (15.93 ± 6.23 versus 12.33 ± 4.07) and submandibular glands (17.65 ± 7.34 versus 13.12 ± 4.62) following treatment, along with transient (n = 6) or permanent (n = 2) xerostomia in 8/32 (25%) patients. In 3/32 patients, nephrotoxicity changed from Grade 2 to 3, whereas neither Grade 4 nephrotoxicity nor hematotoxicity was found. In most patients a good agreement was observed for the visual interpretation of the tracer accumulation between 24 h WB and PET/CT scans. However, no significance could be calculated for baseline-absorbed tumor doses and SUVmax values of tumor lesions. 5/32 (16%) patients showed a mixed response pattern, which resulted in disease progression over time. Conclusion: Serial PSA measurements and post-therapy 24 h WB scintigraphy seems to allow a sufficiently accurate follow-up of 177Lu-PSMA-617-treated mCRPC patients whereas 68Ga-PSMA-11 PET/CT should be performed for patient selection and final response assessment. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the use of 68Ga-PSMA PET/CT for monitoring response to 177Lu-617 PSMA radioligand therapy in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods: Patients from the University Hospital Bonn and the University Hospital Aachen were retrospectively reviewed for this study. We included 48 patients with mCRPC who were treated with 177Lu-PSMA-617 and whose records included 68Ga-PSMA PET/CT imaging before the first and after the third or fourth treatment cycle. A treatment response based on 68Ga-PSMA PET/CT was defined according to a modified version of the PERCIST criteria. A decline in PSA level of ≥50% was considered the reference standard. The sensitivity, specificity, positive and negative predictive values, and ROC curves were calculated, and patient survival times in relation to the PET results were also analysed. Results: 68Ga-PSMA PET/CT had a sensitivity of about 85% and a specificity of between 55% and 65%. The negative and positive predictive values ranged between 70% and 78%. The fitted ROC area was 0.70. The survival time was about 19.6 months in patients with a treatment response, while nonresponders had a survival time of about 15.9 months. However, this difference between the groups was not statistically significant. Conclusion: Our results indicate that 68Ga-PSMA PET/CT could be a useful tool for the evaluation of response to 177Lu-PSMA-617 radioligand therapy within a theranostic framework. [ABSTRACT FROM AUTHOR]

177 Lu-PSMA-617 is an effective therapeutic option in metastasized castration-resistant prostate cancer (mCRPC). However, some patients progress under treatment. We hypothesized that the tracer kinetics within the metastases may influence the therapy effectiveness and tested this hypothesis by analyzing uptake parameters on 2 consecutive posttherapy SPECT/CT scans. Methods: mCRPC patients treated with 177 Lu-PSMA-617 and with available posttherapy SPECT/CT imaging (24 and 48 h after the first treatment) were enrolled retrospectively. Volumes of interest were defined on lymph node metastasis (LNM) and bone metastasis (BM) on both SPECT/CT scans. The reduction of the percentage injected dose (%IDred) between the 2 SPECT/CT scans was computed. We compared %IDred of responders (prostate-specific antigen drop ≥ 50% after 2 cycles of 177 Lu-PSMA-617) and nonresponders. We tested the association of %IDred with progression-free survival and overall survival (OS) using a univariate Kaplan-Meier (KM) analysis and a multivariate Cox regression model. Results: Fifty-five patients (median age, 73 y; range, 54-87 y) were included. %IDred in LNM and BM was greater in nonresponders than in responders (for LNM, 36% in nonresponders [interquartile range (IQR), 26%-47%] vs. 24% in responders [IQR, 12%-33%] [ P = 0.003]; for BM, 35% in nonresponders [IQR, 27%-52%] vs. 18% in responders [IQR, 15%-29%] [ P = 0.002]). For progression-free survival, in KM analysis, greater %IDred in LNM ( P = 0.008) and BM ( P = 0.001) was associated with shorter survival, whereas in multivariate analysis, only %IDred in LNM was retained ( P = 0.03). In univariate KM analysis of OS, greater %IDred in BM was associated with shorter survival ( P = 0.002). In multivariate OS analysis, BM %IDred ( P = 0.009) was retained. Conclusion: The 177 Lu-PSMA-617 clearance rate from mCRPC metastases appears to be a relevant prognosticator of response and survival, with faster clearing possibly signaling a shorter radiopharmaceutical residence time and absorbed dose. Dual-time-point analysis appears to be a feasible and readily available approach to estimate the likelihood of response and patients' survival., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)