Martin Bögemann

German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients

177Lu-labeled PSMA-617 is a promising new therapeutic agent for radioligand therapy (RLT) of patients with metastatic castration-resistant prostate cancer (mCRPC). Initiated by the German Society of Nuclear Medicine, a retrospective multicenter data analysis was started in 2015 to evaluate efficacy and safety of 177Lu-PSMA-617 in a large cohort of patients. Methods: One hundred forty-five patients (median age, 73 y; range, 43–88 y) with mCRPC were treated with 177Lu-PSMA-617 in 12 therapy centers between February 2014 and July 2015 with 1–4 therapy cycles and an activity range of 2–8 GBq per cycle. Toxicity was categorized by the common toxicity criteria for adverse events (version 4.0) on the basis of serial blood tests and the attending physician’s report. The primary endpoint for efficacy was biochemical response as defined by a prostate-specific antigen decline ≥ 50% from baseline to at least 2 wk after the start of RLT. Results: A total of 248 therapy cycles were performed in 145 patients. Data for biochemical response in 99 patients as well as data for physician-reported and laboratory-based toxicity in 145 and 121 patients, respectively, were available. The median follow-up was 16 wk (range, 2–30 wk). Nineteen patients died during the observation period. Grade 3–4 hematotoxicity occurred in 18 patients: 10%, 4%, and 3% of the patients experienced anemia, thrombocytopenia, and leukopenia, respectively. Xerostomia occurred in 8%. The overall biochemical response rate was 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle. Elevated alkaline phosphatase and the presence of visceral metastases were negative predictors and the total number of therapy cycles positive predictors of biochemical response. Conclusion: The present retrospective multicenter study of 177Lu-PSMA-617 RLT demonstrates favorable safety and high efficacy exceeding those of other third-line systemic therapies in mCRPC patients. Future phase II/III studies are warranted to elucidate the survival benefit of this new therapy in patients with mCRPC.

Comparative Assessment of Urinary Prostate Cancer Antigen 3 and TMPRSS2:ERG Gene Fusion with the Serum [−2]Proprostate-Specific Antigen–Based Prostate Health Index for Detection of Prostate Cancer

BACKGROUND We compared urinary prostate cancer antigen 3 (PCA3), transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) gene fusion (T2:ERG), and the serum [-2]proprostate-specific antigen ([-2]proPSA)-based prostate health index (Phi) for predicting biopsy outcome. METHODS Serum samples and first-catch urine samples were collected after digital rectal examination (DRE) from consented outpatients with PSA 0.5-20 μg/L who were scheduled for prostate biopsy. The PCA3 score (PROGENSA PCA3, Hologic Gen-Probe) and T2:ERG score (Hologic Gen-Probe) were determined. Measurements of serum PSA, free PSA, and [-2]proPSA (Beckman Coulter) were performed, and the percentages of free PSA (%fPSA) and Phi ([-2]proPSA/fPSA × √PSA) were determined. RESULTS Of 246 enrolled men, prostate cancer (PCa) was diagnosed in 110 (45%) and there was no evidence of malignancy (NEM) in 136 (55%). A first set of biopsies was performed in 136 (55%) of all men, and 110 (45%) had ≥1 repeat biopsies. PCA3, Phi, and T2:ERG differed significantly between men with PCa and NEM, and these markers showed the largest areas under the ROC curve (AUCs) (0.74, 0.68, and 0.63, respectively). PCA3 had the largest AUC of all parameters, albeit not statistically different from Phi. Phi showed somewhat lower specificities than PCA3 at 90% sensitivity. Combination of both markers enhanced diagnostic power with modest AUC gains of 0.01-0.04. Although PCA3 had the highest AUC in the repeat-biopsy cohort, the highest AUC for Phi was observed in DRE-negative patients with PSA in the 2-10 μg/L range. CONCLUSIONS PCA3 and Phi were superior to the other evaluated parameters but their combination gave only moderate enhancements in diagnostic accuracy for PCa at first or repeat prostate biopsy.

Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1

PURPOSE Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC. PATIENTS AND METHODS Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments. RESULTS A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively). CONCLUSION Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes.

Correlation of Intraprostatic Tumor Extent with 68Ga-PSMA Distribution in Patients with Prostate Cancer

We evaluated the diagnostic value and accuracy of prostate-specific membrane antigen (PSMA) PET for the intraprostatic delineation of prostate cancer before prostatectomy. Methods: We identified 6 patients with biopsy-proven high-risk prostate cancer who were referred for 68Ga-PSMA PET/CT before radical prostatectomy to rule out metastasis. After prostatectomy, a histologic map of the prostate was reconstructed. The histologic extent and Gleason score of each segment of the prostate were compared with 68Ga-PSMA PET images resliced to the histologic axis. Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios were calculated. The SUV of each segment was measured, and median values were compared. Results: Of the 132 segments, 112 were eligible for analysis. The correlation of histologic results with 68Ga-PSMA PET images showed a specificity and sensitivity of 92%. The positive and negative likelihood ratio and the positive and negative predictive value for detection of prostate cancer on 68Ga-PSMA PET were 11.5, 0.09, 96%, and 85%, respectively. The median SUVmax of true-positive prostate segments was significantly higher than that of true-negative segments (11.0 ± 7.8 vs. 2.7 ± 0.9, P < 0.001), and a cutoff of 4 revealed a sensitivity and specificity of 86.5% and an accuracy of 87.5%. Conclusion: These preliminary results show that the intraprostatic localization and extent of prostate cancer may be estimated by 68Ga-PSMA PET. This imaging method may be helpful for identifying target lesions before prostate biopsy and may support decision making before focal or radical therapy.

Radioligand Therapy With 177lu-psma-617 as A Novel Therapeutic Option in Patients With Metastatic Castration Resistant Prostate Cancer

Background Despite progress in treatment of metastatic castration-resistant prostate cancer (mCRPC), new approaches are urgently needed. Recently theranostic concepts using radiolabeled ligands of the prostate-specific membrane antigen (PSMA) have been developed for diagnostics and therapy of patients with advanced mCRPC. The aim of this study was to evaluate tumor response, adverse effects, and survival in patients undergoing radioligand therapy with 177Lu-PSMA-617. Methods Fifty therapies using 177Lu-PSMA-617 were performed in 28 consecutive patients with mCRPC and exhausted conventional therapeutic options (median age, 73.4 years; range, 45–87 years). Data were retrospectively analyzed with focus on response, safety, and survival. The median overall survival was compared with that of a recent historical patient cohort treated with best supportive care prior to availability of 177Lu-PSMA-617. Results Any PSA decline occurred in 59% and 75% of patients after 1 and 2 therapies. Moreover, a PSA decline of 50% or greater occurred in 32% and 50%. Therapies were well tolerated. Hematologic and renal parameters changed insignificantly; permanent xerostomia or other safety-related toxicity did not occur. The estimated median survival was 29.4 weeks, significantly longer than survival in the historical best supportive care group (19.7 weeks [hazard ratio, 0.44; 95% confidence interval, 0.20–0.95]; P = 0.031). Conclusions Results from 50 therapies show that radioligand therapy with 177Lu-PSMA-617 is effective and well tolerated and seems to increase overall survival. A future randomized controlled prospective study will be necessary to confirm these results.

The endothelin axis in urologic tumors : mechanisms of tumor biology and therapeutic implications

Endothelin (ET)-1 and its receptors ET-A and ET-B, referred to commonly as the endothelin axis, have been identified in various human cancers, especially gynecologic tumors, such as breast cancer or ovarian cancer, but also including urologic tumor entities. They play a key role in tumor growth and progression by influencing critical cancer pathways, such as apoptosis, angiogenesis and proliferation. In prostate cancer, overexpression of the ET-A receptor increases with tumor progression, and clinical trials with selective ET-A receptor antagonists, such as atrasentan (ABT-627), have shown promising early results. In preclinical models of bladder cancer, overexpression of the ET axis has been demonstrated and ET-targeting agents are under investigation. This paper reviews the role of the ET axis in human cancers and focuses on preclinical and clinical studies in urologic tumor entities to further define the role of ET-targeting agents as targeted molecular therapy.

Diagnostic value of additional 68Ga-PSMA-PET before 223Ra-dichloride therapy in patients with metastatic prostate carcinoma

PURPOSE Medical imaging plays an important role in selecting patients with metastatic castration-resistant prostate cancer for 223Ra-dichloride therapy of bone metastases. The purpose of this study was to investigate whether 68Ga-PSMA-PET has incremental value over conventional imaging for selecting patients suitable for 223Ra-dichloride therapy. METHODS In 27 consecutive patients referred for 223Ra-dichloride therapy additional 68Ga-PSMA-PET/CT was performed and tracer distribution was evaluated systematically with respect to the detection of visceral metastases and bone metastases with inadequate uptake on bone scintigraphy. RESULTS In 4 patients (15 %) 68Ga-PSMA-PET revealed previously unknown visceral metastases (3 liver, 1 adrenal gland), which changed the therapeutic decision in 2 cases. PET revealed more extended tumour involvement in the bone compared to bone scintigraphy in 9 patients (33 %). In 3 of these, the mismatch was extensive enough to question suitability for 223Ra-dichloride therapy. CONCLUSIONS Additional 68Ga-PSMA-PET as a gatekeeper between conventional staging and 223Ra-dichloride therapy can provide valuable additional information with regard to visceral metastases and tumour manifestations without adequate bone mineral turnover. It may lead to a change in therapeutic management in a significant number of patients and should therefore be considered in future clinical trials.

Expression of PSMA in tumor neovasculature of high grade sarcomas including synovial sarcoma, rhabdomyosarcoma, undifferentiated sarcoma and MPNST

Aims PSMA (prostate specific membrane antigen) is physiologically expressed in normal prostate tissue. It is overexpressed in prostate cancer cells and has been suggested as a target for antibody-based radioligand therapy. As PSMA expression so far has not been systematically analyzed in soft tissue tumors, the current study aims at investigating a large cohort of different subtypes. Methods and Results Immunohistochemistry was used to detect PSMA expression in 779 samples of soft tissue tumors and Ewing sarcoma as a primary bone malignancy. CD34 coexpression was employed to study PSMA expression in the neovasculature. PSMA expression was found in the tumor-associated neovasculature of 151/779 soft tissue/bone tumors (19.38%) and was more frequent in malignant tumors compared to tumors with intermediate or benign biological potential (p=0.078). Strong neovascular PSMA expression was predominantly observed in subsets of different sarcomas including 3/20 rhabdomyosarcomas (15%), 4/21 malignant peripheral nerve sheath tumors (19.05%), 6/16 synovial sarcomas (35.29%) and 6/33 undifferentiated pleomorphic sarcomas (18.18%). Conclusion We conclude that PSMA is expressed in the neovasculature of a subset of soft tissue tumors to a variable extent. Our observation of strong PSMA expression predominantly occurring in sarcomas might provide a rationale to evaluate PSMA-targeted radioligand therapy in these entities.

Comparison of isolation platforms for detection of circulating renal cell carcinoma cells

Background Analysis of circulating tumor cells (CTCs) has progressed in several tumor entities. However, little is known about CTCs in clear cell renal cell carcinoma (ccRCC) patients. Aim of our studies was to build a stable in vitro fundament for isolation of CTCs in ccRCC. Methods We compared the analytical performance of different CTC isolation methods with regard to yield and purity: EpCAM based enrichment, leukocyte depletion and size based enrichment. EpCAM and cytokeratin 8 (KRT8) as biomarker for CTCs expression were evaluated in ccRCC cell lines as well as clinical samples. Results While the EpCAM based approach failed to successfully isolate tumor cells, CD45 based approaches showed intermediate recovery rates. The cell-size based Parsortix system showed highest recovery rates. EpCAM expression was low or absent in most cell lines as well as in clinical samples, whereas KRT8 was detected as a potential biomarker in ccRCC. Conclusion EpCAM based approaches might miss a high number of CTCs due to low or absent expression of EpCAM in ccRCC, as shown in cell lines as well as in patient samples. We identified the cell-sized based, label independent Parsortix system to be the most effective recovery system for ccRCC CTCs.

Advantage of 18 F-PSMA-1007 over 68 Ga-PSMA-11 PET imaging for differentiation of local recurrence vs. urinary tracer excretion

Local recurrence of prostate cancer after primary local therapy presents challenges for urologists and imaging procedures, especially in patients with low prostatespecific antigen (PSA) values. Recently, Ga prostatespecific membrane antigen (PSMA)-11 has shown promising detection rates, and is gaining adoption worldwide in clinical routine [1]. However, there are a significant number of patients in whom local recurrence cannot be differentiated from activity by urinary tracer excretion. The use of F–PSMA-1007 was recently presented, and showed a delayed renal excretion [2], which may aid clinicians in making meaningful decisions regarding therapy management in these patients. Here we present images of a 74-year-old prostate cancer patient after radical prostatectomy (Gleason score 9) with biochemical recurrence (PSA: 2.1 ng/dl). Images A and B show Ga-PSMA-11 PET-CT (A: maximum-intensity projection, MIP; B: fused axial PET-CT image). Arrows show minimal pararectal uptake close to the bladder and the ureter, for which clinical decision making is problematic. Images C and D show F–PSMA-1007 PET-CT of the same patient (C: MIP, D: fused axial PET-CT image). Arrows show unequivocal focal uptake representing a local recurrence, with high contrast (maximum standard uptake value: 9.9), with no distracting ureteral or vesical excretion activity. F–PSMA-1007 seems to be superior to Ga-PSMA-11 in cases of biochemical recurrence and unclear lesions close to the ureter or urinary bladder.