Visual and whole-body quantitative analyses of 68 Ga-DOTATATE PET/CT for prognosis of outcome after PRRT with 177Lu-DOTATATE.

BACKGROUND: Somatostatin receptors (SSTR) represent an ideal target for nuclear theranostics applications in neuroendocrine tumors (NET). Studies suggest that high uptake on SSTR-PET is associated with response to SSTR peptide receptor radionuclide therapy (PRRT). The purpose of this study was to evaluate the role of baseline whole-body (WB) 68 Ga-DOTATATE PET/CT (SSTR-PET) quantitative parameters, and the presence of NET lesions without uptake on SSTR-PET, as outcome prognosticator in patients with NET treated with PRRT. METHODS: Patients with NET who underwent at least 4 177Lu-DOTATATE PRRT cycles between 07/2016 and 03/2021 were included in this retrospective analysis if they fulfilled the following inclusion criteria: SSTR-PET within 6 months of 1st PRRT cycle, follow-up CT and/or MRI performed > 6 months after the 4th cycle of PRRT. The SSTR-PET analysis consisted of a visual and a quantitative analysis done independently by two board-certified physicians. The visual analysis assessed the presence of NET lesions visible on the SSTR-PET co-registered CT. The quantitative analysis consisted in contouring all SSTR-avid lesions on SSTR-PET and extracting WB quantitative parameters: SUVmean (WB-SUVmean), SUVmax of the lesion with highest uptake (H-SUVmax), and tumor volume (WB-TV). WB-SSTR-PET parameters and the presence of SSTR-PET-negative lesions were correlated to radiologic response (assessed by RECIST 1.1 criteria) and progression-free survival (PFS). Fisher's exact test, Mann-Whitney's U test and Kaplan-Meier curves with Cox-regression analysis were used for the statistical analysis. RESULTS: Forty patients (F/M: 21/19; 34/40 with gastro-entero-pancreatic (GEP) NET, 6/40 with non-GEP NET) were included in the analysis. The median follow-up period after the 4th PRRT cycle was 25.7 months (range 15.2-59.1). Fourteen/40 (35%) patients showed radiologic response (RECIST PR). PFS event was observed in 17/40 (42.5%) patients. Thirteen/40 (32.5%) patients had SSTR-PET-negative lesions at baseline. Higher WB-SUVmean and H-SUVmax were associated with better response (p = 0.015 and 0.005, respectively). The presence of SSTR-PET-negative lesions and lower WB-SUVmean were associated with shorter PFS (p = 0.026 and 0.008, respectively). CONCLUSION: Visual and quantitative analyses of baseline SSTR-PET can yield valuable information to prognosticate outcomes after 177Lu-DOTATATE PRRT.

Associations of quantitative whole-body PSMA-PET metrics with PSA progression status under long-term androgen deprivation therapy in prostate cancer patients: a retrospective single-center study.

PURPOSE: To evaluate whether quantitative whole-body (WB) PSMA-PET metrics under long-term androgen deprivation therapy (ADT) and/or androgen receptor signaling inhibitors (ARSi) are associated with PSA progression. METHODS: Patients who underwent at least 2 68Ga-PSMA-11 PET/CT scans between October 2016 and April 2021 (n = 372) and started a new line of ADT ± ARSi between PET1 and PET2 were retrospectively screened for inclusion. We investigated the association between PCWG3-defined PSA progression status at PET2 and the following PSMA-PET parameters: appearance of new lesions on PET2, ≥ 20% increase in WB-PSMA tumor volume (WB-PSMA-VOL), progression of disease (PD) by RECIP 1.0, and ≥ 30% increase in WB-PSMA-SUVmean from PET1 to PET2. Spearman's rank correlation coefficients and Fisher's exact test were used to evaluate the associations. RESULTS: Thirty-five patients were included: 12/35 (34%) were treated with ADT only and 23/35 (66%) with ARSi ± ADT. The median time between PET1 and PET2 was 539 days. Changes (%) in median PSA levels, WB-PSMA-SUVmean, and WB-PSMA-VOL from PET1 to PET2 were -86%, -23%, and -86%, respectively. WB-PSMA-VOL ≥ 20%, new lesions, RECIP-PD, and WB-PSMA-SUVmean ≥ 30% were observed in 5/35 (14%), 9/35 (26%), 5/35 (14%), and 4/35 (11%) of the whole cohort, in 3/9 (33%), 7/9 (78%), 3/9 (33%), and 2/9 (22%) of patients with PSA progression at PET2, and in 2/26 (8%), 2/26 (8%), 2/26 (8%), and 2/26 (8%) of patients without PSA progression at PET2 (p = 0.058, p < 0.001, p = 0.058, p = 0.238, respectively). Changes in PSA were correlated to percent changes in WB-PSMA-VOL and WB-PSMA-SUVmean (Spearman ρ: 0.765 and 0.633, respectively; p < 0.001). CONCLUSION: Changes in PSA correlated with changes observed on PSMA-PET, although discordance between PSA and PSMA-PET changes was observed. Further research is necessary to evaluate if PSMA-PET parameters can predict progression-free survival and overall survival and serve as novel endpoints in clinical trials.

Prognostic Value of End-of-Treatment PSMA PET/CT in Patients Treated with 177Lu-PSMA Radioligand Therapy: A Retrospective, Single-Center Analysis.

Our objective was to evaluate the prognostic value of end-of-treatment prostate-specific membrane antigen (PSMA) PET/CT (PSMA-PET) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA radioligand therapy (PSMA-RLT). Methods: This was a single-center retrospective study. mCRPC patients who underwent PSMA-RLT with available baseline PSMA-PET (bPET) and end-of-treatment PSMA-PET (ePET) within 6 mo of the last PSMA-RLT cycle were eligible. Overall survival (OS) and prostate-specific antigen (PSA) progression status at the time of ePET (by Prostate Cancer Clinical Trials Working Group 3 criteria) were collected. PSMA-PET tumor segmentation was performed to obtain whole-body PSMA tumor volume (PSMA-VOL) and define progressive (≥20% increase) versus nonprogressive disease. Pairs of bPET and ePET were interpreted for appearance of new lesions. Response Evaluation Criteria in PSMA-PET/CT (RECIP) 1.0 were also applied to define progressive versus nonprogressive disease. The associations between changes in PSMA-VOL, new lesions, RECIP 1.0, and PSA progression status at the time of ePET with OS were evaluated by Kaplan-Meier analysis. Results: Twenty mCRPC patients were included. The median number of treatment cycles was 3.5 (interquartile range [IQR], 2-4). The median time between bPET and cycle 1 of PSMA-RLT was 1.0 mo (IQR, 0.7-1.8 mo). The median time between the last cycle of PSMA-RLT and ePET was 1.9 mo (IQR, 1.2-3.5 mo). Twelve of 20 patients (60%) had died at the last follow-up. The median follow-up time from ePET for survivors was 31.2 mo (IQR, 6.8-40.7 mo). The median OS from ePET was 11.4 mo (IQR, 6.8-30.7 mo). Patients with new lesions on ePET had shorter OS than those without new lesions (median OS, 10.7 mo [95% CI, 9.2-12.2] vs. not reached; P = 0.002). Patients with progressive PSMA-VOL had shorter OS than those with nonprogressive PSMA-VOL (median OS, 10.7 mo [95% CI: 9.7-11.7 mo] vs. not reached; P = 0.007). Patients with progressive RECIP had shorter OS than those with nonprogressive RECIP (median OS, 10.7 mo [95% CI, 9.7-11.7 mo] vs. not reached; P = 0.007). PSA progression at the time of ePET was associated with shorter OS (median, 10.9 mo [95% CI, 9.4-12.4 mo] vs. not reached; P = 0.028). Conclusion: In this retrospective study of 20 mCRPC patients treated with PSMA-RLT, progression on ePET by the appearance of new lesions, changes in PSMA-VOL, and RECIP 1.0 was prognostic for OS. Validation in larger, prospective multicentric clinical trials is warranted.

Developing a Patient-Reported Outcome Measure for Radionuclide Therapy for Prostate Cancer.

The field of radionuclide therapy (RNT) for prostate cancer (PC) is growing rapidly, with recent Food and Drug Administration approval of the first 177Lu-PSMA ligand. We aimed to develop the first patient-reported outcome (PRO) measure for PC patients receiving RNT. Methods: We identified relevant symptoms and toxicities by reviewing published trials and interviews with PC patients receiving RNT (n = 29), caregivers (n = 14), and clinicians (n = 11). Second, we selected items for measure inclusion. Third, we refined the item list with input from experts in RNTs and PROs. Fourth, we finalized the Functional Assessment of Cancer Therapy-Radionuclide Therapy (FACT-RNT) with patient input. Results: This multistep process yielded a brief 15-item measure deemed by key stakeholders to be relevant and useful in the context of RNT for PC. Conclusion: The FACT-RNT is a new standardized tool to monitor relevant symptoms and toxicities among PC patients in RNT trials and real-world settings.

Identifying the Best Candidates for Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography as the Primary Staging Approach Among Men with High-risk Prostate Cancer and Negative Conventional Imaging.

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is an emerging imaging modality with greater sensitivity and specificity over conventional imaging for prostate cancer (PCa) staging. Using data from two prospective trials (NCT03368547 and NCT04050215), we explored predictors of overall upstaging (nodal and metastatic) by PSMA PET/CT among patients with cN0M0 National Comprehensive Cancer Network high-risk PCa on conventional imaging (n = 213). Overall, 21.1%, 8.9%, and 23.9% of patients experienced nodal, metastatic, and overall upstaging, respectively, without histologic confirmation. On multivariable analysis, Gleason grade group (GG) and percent positive core (PPC) on systematic biopsy significantly predict overall upstaging (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.33-3.45; p = 0.002; and OR 1.03, 95% CI 1.01-1.04; p < 0.001). Overall upstaging was significantly more frequent among men with GG 5 disease (33.0% vs. 17.6%; p = 0.0097) and PPC ≥50% (33.0% vs 15.0%; p = 0.0020). We constructed a nomogram that predicts overall upstaging using initial prostate-specific antigen, PPC, GG, and cT stage, with coefficients estimated from a standard logistic regression model (using maximum likelihood estimation). It is internally validated with a tenfold cross-validated area under the receiver operating characteristic curve estimated at 0.74 (95% CI 0.67-0.82). In our cohort, 90% of patients who had a nomogram-estimated risk below the cutoff of 22% for overall upstaging could have been spared PSMA PET/CT as our model correctly predicted no upstaging. In other words, the predictive model only missed 10% of patients who would otherwise have benefitted from PSMA PET/CT. PATIENT SUMMARY: We analyzed predictors of overall upstaging (lymph node or/and metastasis) by prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) from conventional imaging in men with high-risk prostate cancer undergoing initial staging deemed free of disease in the lymph nodes and distant metastasis by conventional imaging techniques. We found that the pathologic grade and disease burden in a prostate biopsy are associated with upstaging. We also developed a tool that predicts the probability of upstaging according to an individual patient's characteristics. Our study may help in defining patient groups who are most likely to benefit from the addition of a PSMA PET/CT scan.

Safety of PSMA-Targeted Molecular Radioligand Therapy with 177Lu-PSMA-617: Results from the Prospective Multicenter Phase 2 Trial RESIST-PC (NCT03042312).

The purpose of this analysis was to report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results: The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of 177Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion:177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.

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.

Prospective phase 2 trial of PSMA-targeted molecular RadiothErapy with 177Lu-PSMA-617 for metastatic castration-reSISTant Prostate Cancer (RESIST-PC): efficacy results of the UCLA cohort.

The objective of this study was to determine prospectively the efficacy profile of 2 activity regimens of 177Lu-PSMA therapy in patients with progressive metastatic castrate-resistant prostate cancer (mCRPC): 6.0 vs. 7.4 GBq. Methods: RESIST-PC (NCT03042312) was a prospective multicenter phase 2 trial. Patients with progressive mCRPC after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, and sufficient PSMA expression by PSMA PET were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq) and received up to 4 cycles every 8 wk. The primary endpoint was the efficacy of 177Lu-PSMA measured by the prostate-specific antigen (PSA) response rate (RR) after 2 cycles (≥50% decline from baseline). Secondary endpoints included the PSA RR (≥50% decline) at any time (best response), and overall survival (OS). Results: The study was closed at enrollment of 71/200 planned patients because of sponsorship transfer. We report here the efficacy of the University of California Los Angeles cohort results only (n = 43). The PSA RRs after 2 cycles and at any time were 11/40 (28%, 95% CI 15-44), 6/13 (46%, 95% CI 19-75), and 5/27 (19%, 95% CI 6-38), and 16/43 (37%, 95% CI 23-53), 7/14 (50%, 95% CI 23-77), and 9/29 (31%, 95% CI 15-51) in the whole cohort, the 6.0-GBq group, and the 7.4-GBq group, respectively (P = 0.12 and P = 0.31). The median OS was 14.0 mo (95% CI 10.1-17.9), 15.8 (95% CI 11.8-19.4), and 13.5 (95% CI 10.0-17.0) in the whole cohort, the 6.0-GBq group, and the 7.4 GBq group, respectively (P = 0.87). OS was longer in patients who experienced a PSA decline ≥ 50% at any time than in those who did not: median, 20.8 versus 10.8 mo (P = 0.005). Conclusion: In this prospective phase 2 trial of 177Lu-PSMA for mCRPC, the median OS was 14 mo. Despite the heterogeneous study population and the premature study termination, the efficacy profile of 177Lu-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 177Lu-PSMA therapy administration scheme to improve tumor radiation dose delivery and efficacy.

The Impact of Monosodium Glutamate on 68Ga-PSMA-11 Biodistribution in Men with Prostate Cancer: A Prospective Randomized, Controlled Imaging Study.

The prostate-specific membrane antigen (PSMA) has been targeted for PET imaging and radioligand therapy (RLT) in patients with prostate cancer. Xerostomia is a common side effect of RLT because of the high salivary gland uptake of PSMA radioligands. Here, we aimed to determine the impact of monosodium glutamate (MSG) administration on PSMA-radioligand biodistribution within healthy organs and tumor lesions by using 68Ga-PSMA-11 PET imaging. Methods: Sixteen men with prostate cancer were randomized (1:1) into oral ingestion and oral topical application ("swishing") arms. Each subject underwent 2 68Ga-PSMA-11 PET/CT scans within 14 d under baseline and MSG conditions. The salivary glands and whole-body tumor lesions were segmented using qPSMA software. We quantified tracer uptake via SUVmean and SUVmax and compared parameters within each patient. Results: For the oral ingestion arm, salivary gland SUVmean and SUVmax decreased on average from the control scan to the MSG scan by 45% ± 15% (P = 0.004) and 53% ± 11% (P < 0.001), respectively. Tumor lesion SUVmean and SUVmax also decreased by 38% (interquartile range, -67% to -33%) and -52% (interquartile range, -70% to -49%), respectively (P = 0.018). Swishing had no significant effect on 68Ga-PSMA-11 accumulation in normal organs or tumor lesions. Conclusion: Oral ingestion but not topical application of MSG reduced 68Ga-PSMA-11 uptake in salivary glands. Tumor uptake also declined; therefore, the clinical application of MSG is unlikely to be useful in the framework of RLT.