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. MethodsIn 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.

Peptide receptor radiotherapy (PRRT) with somatostatin analogs has been successfully utilized as a treatment for somatostatin overexpressing tumors for years. Treatment of neuroendocrine tumors (NETs) with the beta particle emitter 177 Lu-DOTATATE is currently considered the standard of care for subjects with gastroenteropancreatic NETs (GEP-NETs). Despite the success of 177 Lu-DOTATATE, there remains significant room for improvement in terms of both safety and efficacy. Targeted alpha-emitter therapy with isotopes such as lead-212 ( 212 Pb) has the potential to improve both. Herein, we present the preliminary results of the phase 1 first-in-human dose-escalation trial evaluating 212 Pb-DOTAMTATE in patients with somatostatin receptor positive NETs.Methods: A total of 20 subjects with histologically confirmed NETs, prior positive somatostatin analogue scans, and no prior history of 177 Lu/ 90 Y/ 111 In PRRT, with different primary sites of the disease, were enrolled. Treatment began with single ascending doses of 212 Pb-DOTAMTATE, with subsequent cohorts receiving an incremental 30% dose increase, which was continued until a tumor response or a dose-limiting toxicity was observed. This was followed by a multiple ascending dose regimen. The recommended phase 2 dose (RP2D) regimen consisted of 4 cycles of 2.50 MBq/kg (67.6 µCi/kg) of 212 Pb-DOTAMTATE administrated at 8-week intervals, intravenously.Results: Ten subjects received the highest dose of 2.50 MBq/kg/cycle (67.6 µCi/kg/cycle). Treatment was well tolerated, with the most common treatment-emergent adverse events (TEAEs) being nausea, fatigue, and alopecia.No serious TEAEs were related to the study drug, and no subjects required treatment delay or a dose reduction. An objective radiological response (ORR) of 80% was observed for the first 10 subjects treated at the RP2D. Conclusion:Targeted alpha therapy with 212 Pb-DOTAMTATE has been shown to be well-tolerated.Preliminary efficacy results are highly promising. If these results are confirmed in a larger, multicenter clinical trial, it would provide a substantial benefit over currently FDA approved therapies for patients with metastatic or inoperable SSTR-expressing NETs regardless of the grade and location of the primary tumor.

Background:We aimed to systematically determine the impact of tumor burden on the 68 Ga-prostate-specific membrane antigen-11 ( 68 Ga-PSMA) PET biodistribution by the use of quantitative measurements.Methods: This international multicenter retrospective analysis included 406 men with prostate cancer who received 68 Ga-PSMA PET/CT. Of these, 356 had positive findings and were stratified by quintiles into very low (Q1, ≤25 ml), low (Q2, 25-189 ml), moderate (Q3, 189-532 ml), high (Q4, 532-1355 ml) and very high (Q5, ≥1355 ml) total PSMApositive tumor volume (PSMA-VOL). PSMA-VOL was obtained by semi-automatic segmentation of total tumor lesions using qPSMA software. Fifty prostate cancer patients with no PSMA-positive lesions (negative scan) served as control group. Normal organs, which included salivary glands, liver, spleen and kidneys, were semi-automatically segmented using 68 Ga-PSMA PET images and average SUV (SUVmean) was obtained.Correlations of PSMA-VOL as continuous and as categorical variable by quintiles with SUVmean of normal organ were evaluated. Results:The median PSMA-VOL was 302 ml (interquartile range [IQR], 47-1076). The median (IQR) SUVmean of salivary glands, kidneys, liver and spleen was 10.

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Lu-PSMA for mCRPC, the median OS was 14 mo. Despite the heterogeneous study population and the premature study termination, the efficacy profile of 177 Lu-PSMA appeared to be favorable and comparable with both activity regimens (6.0 vs. 7.4 GBq). Results justify confirmation with real-world data matched-pair analysis and further clinical trials to refine and optimize the 177 Lu-PSMA therapy administration scheme to improve tumor radiation dose delivery and efficacy.