[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Long-Term Follow-up and Outcomes of Retreatment in an Expanded 50-Patient Single-Center Phase II Prospective Trial of 177Lu-PSMA-617 Theranostics in Metastatic Castration-Resistant Prostate Cancer.

177Lu-PSMA-617 is a radioligand with high affinity for prostate-specific membrane antigen (PSMA), enabling targeted ß-irradiation of prostate cancer. We have previously reported favorable activity with low toxicity in a prospective phase II trial involving 30 men with metastatic castration-resistant prostate cancer. We now report their longer-term outcomes, including a 20-patient extension cohort and outcomes of subsequent systemic treatments after completion of trial therapy. Methods: Fifty patients with PSMA-avid metastatic castration-resistant prostate cancer who had progressed after standard therapies received up to 4 cycles of 177Lu-PSMA every 6 wk. Endpoints included prostate-specific antigen (PSA) response (Prostate Cancer Working Group 2), toxicity (Common Terminology Criteria for Adverse Events, version 4.03), imaging response, patient-reported health-related quality of life, progression-free survival, and overall survival. We also describe, as a novel finding, outcomes of men who subsequently progressed and had further systemic therapies, including 177Lu-PSMA. Results: Seventy-five men were screened to identify 50 patients eligible for treatment. Adverse prognostic features of the cohort included short median PSA doubling time (2.3 mo) and extensive prior treatment, including prior docetaxel (84%), cabazitaxel (48%), and abiraterone or enzalutamide (92%). The mean administered radioactivity was 7.5 GBq/cycle. A PSA decline of at least 50% was achieved in 32 of 50 patients (64%; 95% confidence interval [CI], 50%-77%), including 22 patients (44%; 95% CI, 30%-59%) with at least an 80% decrease. Of 27 patients with measurable soft-tissue disease, 15 (56%) achieved an objective response by RECIST 1.1. The most common toxicities attributed to 177Lu-PSMA were self-limiting G1-G2 dry mouth (66%), transient G1-G2 nausea (48%), G3-G4 thrombocytopenia (10%), and G3 anemia (10%). Brief Pain Inventory severity and interference scores decreased at all time points, including at the 3-mo follow-up, with a decrease of -1.2 (95% CI, -0.5 to -1.9; P = 0.001) and -1.0 (95% CI, -0.2 to -0.18; P = 0.013), respectively. At a median follow-up of 31.4 mo, median overall survival was 13.3 mo (95% CI, 10.5-18.7 mo), with a significantly longer survival of 18.4 mo (95% CI, 13.8-23.8 mo) in patients achieving a PSA decline of at least 50%. At progression after prior response, further 177Lu-PSMA was administered to 15 (30%) patients (median of 2 cycles commencing 359 d from enrollment), with a PSA decline of at least 50% in 11 patients (73%). Four of 21 patients (19%) receiving other systemic therapies on progression experienced a PSA decline of at least 50%. There were no unexpected adverse events with 177Lu-PSMA retreatment. Conclusion: This expanded 50-patient cohort of men with extensive prior therapy confirms our earlier report of high response rates, low toxicity, and improved quality of life with 177Lu-PSMA radioligand therapy. On progression, rechallenge 177Lu-PSMA demonstrated higher response rates than other systemic therapies.

Dosimetry of 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer: Correlations Between Pretherapeutic Imaging and Whole-Body Tumor Dosimetry with Treatment Outcomes.

177Lu-prostate-specific membrane antigen (PSMA)-617 enables targeted delivery of ß-particle radiation to prostate cancer. We determined its radiation dosimetry and relationships to pretherapeutic imaging and outcomes. Methods: Thirty patients with prostate cancer receiving 177Lu-PSMA-617 within a prospective clinical trial (ACTRN12615000912583) were studied. Screening 68Ga-PSMA-11 PET/CT demonstrated high PSMA expression in all patients. After therapy, patients underwent quantitative SPECT/CT at 4, 24, and 96 h. Pharmacokinetic uptake and clearance at a voxel level were calculated and translated into absorbed dose using voxel S values. Volumes of interest were drawn on normal tissues and tumor to assess radiation dose, and a whole-body tumor dose was defined. Correlations between PSMA PET/CT parameters, dosimetry, and biochemical and therapeutic response were analyzed to identify relationships between absorbed dose, tumor burden, and patient physiology. Results: Mean absorbed dose to kidneys, submandibular and parotid glands, liver, spleen, and bone marrow was 0.39, 0.44, 0.58, 0.1, 0.06, and 0.11 Gy/MBq, respectively. Median whole-body tumor-absorbed dose was 11.55 Gy and correlated with prostate-specific antigen (PSA) response at 12 wk. A median dose of 14.1 Gy was observed in patients achieving a PSA decline of at least 50%, versus 9.6 Gy for those achieving a PSA decline of less than 50% (P < 0.01). Of 11 patients receiving a tumor dose of less than 10 Gy, only one achieved a PSA response of at least 50%. On screening PSMA PET, whole-body tumor SUVmean correlated with mean absorbed dose (r = 0.62), and SUVmax of the parotids correlated with absorbed dose (r = 0.67). There was an inverse correlation between tumor volume and mean dose to the parotids (r = -0.41) and kidneys (r = -0.43). The mean parotid dose was also reduced with increasing body mass (r = -0.41) and body surface area (r = -0.37). Conclusion:177Lu-PSMA-617 delivers high absorbed doses to tumor, with a significant correlation between whole-body tumor dose and PSA response. Patients receiving less than 10 Gy were unlikely to achieve a fall in PSA of at least 50%. Significant correlations between aspects of screening 68Ga-PET/CT and tumor and normal tissue dose were observed, providing a rationale for patient-specific dosing. Reduced salivary and kidney doses were observed in patients with a higher tumor burden. The parotid dose also reduced with increasing body mass and body surface area.

Risk stratification in the investigation of pulmonary nodules in a high-risk cohort: positron emission tomography/computed tomography outperforms clinical risk prediction algorithms.

BACKGROUND: Clinical prediction models and 18-fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) are used for the assessment of solitary pulmonary nodules (SPN); however, a biopsy is still required before treatment, which carries risk. AIM: To determine the combined predictive benefit of one such model combined with modern PET/CT data to improve decision-making about biopsy prior to treatment and possibly reduce costs. METHODS: Patients with a SPN undergoing 18F-FDG-PET/CT from January 2011 to December 2012 were retrospectively identified; 143 patients met inclusion criteria. PET/CT studies were rated (5-point visual scale), and CT characteristics were determined. Tissue was obtained by endobronchial ultrasonography with guide sheath (EBUS-GS), CT-guided biopsy and/or surgery. EBUS-transbronchial needle aspiration (TBNA) was used instead of nodule biopsy if there were PET-positive sub-centimetre lymph nodes. RESULTS: The prediction model yielded an area under the receiver operating characteristic curve (AUC-ROC) of 64% (95% confidence interval (CI) 0.55-0.75). PET/CT increased this to 75% (95% CI 0.65-0.84). The 11% improvement is statistically significant. PET/CT score was the best single predictor for malignancy. A PET score of 1-2 had a specificity of 100% (CI 0.73-1.0), whereas a score of 4-5 had a sensitivity of only 76% (CI 0.68-0.84). No significant difference in clinical prediction scores between groups was noted. PET/CT showed the greatest benefit in true negatives and in detecting small mediastinal lymph nodes to allow EBUS-TBNA with a higher diagnostic rate. Cost analysis did not support a policy of resection-without-tissue diagnosis. CONCLUSION: PET/CT improves the clinical prediction of SPN, but its greatest use is in proving benignity. High PET scores had high false positive rates and did not add to clinical prediction. PET should be incorporated early in decision-making to allow for more effective biopsy strategies.

Optical differentiation between malignant and benign lymphadenopathy by grey scale texture analysis of endobronchial ultrasound convex probe images.

BACKGROUND: Morphologic and sonographic features of endobronchial ultrasound (EBUS) convex probe images are helpful in predicting metastatic lymph nodes. Grey scale texture analysis is a well-established methodology that has been applied to ultrasound images in other fields of medicine. The aim of this study was to determine if this methodology could differentiate between benign and malignant lymphadenopathy of EBUS images. METHODS: Lymph nodes from digital images of EBUS procedures were manually mapped to obtain a region of interest and were analyzed in a prediction set. The regions of interest were analyzed for the following grey scale texture features in MATLAB (version 7.8.0.347 [R2009a]): mean pixel value, difference between maximal and minimal pixel value, SEM pixel value, entropy, correlation, energy, and homogeneity. Significant grey scale texture features were used to assess a validation set compared with fluoro-D-glucose (FDG)-PET-CT scan findings where available. RESULTS: Fifty-two malignant nodes and 48 benign nodes were in the prediction set. Malignant nodes had a greater difference in the maximal and minimal pixel values, SEM pixel value, entropy, and correlation, and a lower energy (P < .0001 for all values). Fifty-one lymph nodes were in the validation set; 44 of 51 (86.3%) were classified correctly. Eighteen of these lymph nodes also had FDG-PET-CT scan assessment, which correctly classified 14 of 18 nodes (77.8%), compared with grey scale texture analysis, which correctly classified 16 of 18 nodes (88.9%). CONCLUSIONS: Grey scale texture analysis of EBUS convex probe images can be used to differentiate malignant and benign lymphadenopathy. Preliminary results are comparable to FDG-PET-CT scan.

Tumor thrombus in the great veins from papillary carcinoma of the thyroid: 131I scan findings.

Tumor invasion of great veins and forming thrombus is a rare complication in papillary carcinoma of thyroid. Contrast computed tomography, ultrasound, and positron emission tomography scan can demonstrate the thrombus but will not help to diagnose the nature of the thrombus. Demonstration of the cause of the thrombus by (131)I scan is possible because tumor tissue in the vein will be iodine avid, but simple thrombus will not.