Multiparametric dynamic whole-body PSMA PET/CT using [68Ga]Ga-PSMA-11 and [18F]PSMA-1007.

BACKGROUND: Routine prostate-specific membrane antigen (PSMA) positron emission tomography (PET) performed for primary staging or restaging of prostate cancer patients is usually done as a single static image acquisition 60 min after tracer administration. In this study, we employ dynamic whole-body (D-WB) PET imaging to compare the pharmacokinetics of [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 in various tissues and lesions, and to assess whether Patlak parametric images are quantitative and improve lesion detection and image readability. METHODS: Twenty male patients with prostate cancer were examined using a D-WB PSMA PET protocol. Ten patients were scanned with [68Ga]Ga-PSMA-11 and ten with [18F]PSMA-1007. Kinetic analyses were made using time-activity curves (TACs) extracted from organs (liver, spleen, bone, and muscle) and lesions. For each patient, three images were produced: SUV + Patlak parametric images (Ki and DV). All images were reviewed visually to compare lesion detection, image readability was quantified using target-to-background ratios (TBR), and Ki and DV values were compared. RESULTS: The two PSMA tracers exhibited markedly different pharmacokinetics in organs: reversible for [68Ga]Ga-PSMA-11 and irreversible for [18F]PSMA-1007. For both tracers, lesions kinetics were best described by an irreversible model. All parametric images were of good visual quality using both radiotracers. In general, Ki images were characterized by reduced vascular signal and increased lesion TBR compared with SUV images. No additional malignant lesions were identified on the parametric images. CONCLUSION: D-WB PET/CT is feasible for both PSMA tracers allowing for direct reconstruction of parametric Ki images. The use of multiparametric PSMA images increased TBR but did not lead to the detection of more lesions. For quantitative whole-body Ki imaging, [18F]PSMA-1007 should be preferred over [68Ga]Ga-PSMA-11 due to its irreversible kinetics in organs and lesions.

Recurrence rate after radical prostatectomy following primary staging of high-risk prostate cancer with 68Ga-PSMA PET/CT.

BACKGROUND: Accurate primary staging is one of the most important issues for initial management of prostate cancer (PCa) patients to perform an optimal selection of patients for curative intended treatment. 68Ga-Prostate-Specific-Membrane-Antigen (PSMA) PET/CT was found superior to conventional imaging both for detection of recurrence after curative intended treatment and for primary staging. We studied the recurrence rate after radical prostatectomy in high-risk PCa patients primary staged with 68Ga-PSMA PET/CT compared with conventional imaging. MATERIAL AND METHODS: The study included 247 D'Amico high-risk PCa patients treated with radical prostatectomy (RP) after primary staging with 68Ga-PSMA PET/CT and a reference group of 137 high-risk patients with RP after conventional imaging (99mTc bone scintigraphy and CT). Recurrence rates were assessed by Cox regression and Kaplan-Meier analysis. RESULTS: The 5-year recurrence-free survival rate was 71.1% in the 68Ga-PSMA PET/CT cohort compared with 56.4% in the conventional imaging cohort. Primary staging by 68Ga-PSMA PET/CT reduced biochemical recurrence (BCR) risk by 42% (HR = 0.58 (0.41-0.83), p = .004). CONCLUSION: The present data could indicate a lower recurrence rate after RP following primary staging with 68Ga-PSMA PET/CT compared to conventional imaging, likely due to improved selection of patients for surgery.

A genome-wide CRISPR-Cas9 knockout screen identifies novel PARP inhibitor resistance genes in prostate cancer.

DNA repair gene mutations are frequent in castration-resistant prostate cancer (CRPC), suggesting eligibility for poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. However, therapy resistance is a major clinical challenge and genes contributing to PARPi resistance are poorly understood. Using a genome-wide CRISPR-Cas9 knockout screen, this study aimed at identifying genes involved in PARPi resistance in CRPC. Based on the screen, we identified PARP1, and six novel candidates associated with olaparib resistance upon knockout. For validation, we generated multiple knockout populations/clones per gene in C4 and/or LNCaP CRPC cells, which confirmed that loss of PARP1, ARH3, YWHAE, or UBR5 caused olaparib resistance. PARP1 or ARH3 knockout caused cross-resistance to other PARPis (veliparib and niraparib). Furthermore, PARP1 or ARH3 knockout led to reduced autophagy, while pharmacological induction of autophagy partially reverted their PARPi resistant phenotype. Tumor RNA sequencing of 126 prostate cancer patients identified low ARH3 expression as an independent predictor of recurrence. Our results advance the understanding of PARPi response by identifying four novel genes that contribute to PARPi sensitivity in CRPC and suggest a new model of PARPi resistance through decreased autophagy.

Evaluation of Predictors of Biochemical Recurrence in Prostate Cancer Patients, as Detected by 68Ga-PSMA PET/CT.

OBJECTIVES: To explore the existence of new predictors of the 68Ga-Prostate-Specific Membrane Antigen (PSMA) PET/CT detection rate at biochemical recurrence (BCR) and to determine the detection rate of 68Ga-PSMA PET/CT dependent of prostate-specific antigen (PSA) levels. MATERIALS AND METHODS: In total, 189 PCa patients scanned with 68Ga-PSMA PET/CT for detection of BCR after curatively intended treatment with either radical prostatectomy (n = 153) or radiotherapy (n = 36) were included. Clinicopathological information at the time of diagnosis (PSA, clinical tumor-stage, International Society of Urological Pathology Grade Group and whether 68Ga-PSMA PET/CT was used for primary staging), treatment (RT/RP and histopathology of the prostatectomies), and pre-PET PSA were collected from medical records. RESULTS: Of the 189 68Ga-PSMA PET/CT scans, 103 (54.5%) were positive for BCR of PCa. No significant coherency was observed between detection rate and any clinicopathological variables at diagnosis. Detection rates significantly increased with rising PSA: <0.5 ng/mL = 28%, 0.5 ≤ 1 ng/mL = 39%, 1 ≤ 2 ng/mL = 64%, 2 ≤ 5 ng/mL = 87.5% and ≥5 ng/mL = 97%. CONCLUSIONS: The detection rate of PCa recurrence was strongly dependent of pre-PET PSA levels. None of the additional clinical variables acquired during primary staging, prostatectomy pathology reports, nor primary staging imaging modality affected the detection rate.

68Ga-PSMA PET/CT for Primary Lymph Node and Distant Metastasis NM Staging of High-Risk Prostate Cancer.

With the largest high-risk prostate cancer (PCa) cohort to date undergoing 68Ga-prostate-specific membrane antigen (PSMA) PET/CT primary staging, we aimed to, first, characterize the metastatic spread of PCa in relation to tumor 68Ga-PSMA uptake and the D'Amico classification and, second, compare 68Ga-PSMA PET/CT findings with radical prostatectomy and pelvic lymph node dissection (PLND) histopathology findings. Methods: The study included 691 consecutive newly diagnosed, biopsy-proven, treatment-naïve, D'Amico high-risk PCa patients primary-staged by 68Ga-PSMA PET/CT. PSMA SUVmax and metastatic findings were compared with prostate-specific antigen level, International Society of Urological Pathology (ISUP) grade, and clinical stage as traditional risk stratification parameters. Moreover, 68Ga-PSMA PET/CT findings were compared with histology findings in radical prostatectomy patients undergoing PLND. Undetected lymph node metastases (LNMs) underwent immunohistochemical PSMA staining. Results: Advanced disease (N1/M1) was observed in 35.3% of patients (244/691) and was associated with increasing prostate-specific antigen level, ISUP grade, and clinical stage. LNMs (N1/M1a) were detected in 31.4% (217/691) and bone metastases (M1b) in 16.8% (116/691). Advanced disease frequencies in patients with ISUP grades 2 and 3 were 10.8% (11/102) and 37.1% (33/89), respectively. Risk of advanced disease for cT2a, cT2b, and cT2c tumors was almost equal (24.2%, 27.9%, and 22.4%, respectively). We observed a weak correlation between SUVmax and biopsy ISUP grade (ρ = 0.21; P < 0.001) and a modest correlation between SUVmax and postprostatectomy ISUP grade (ρ = 0.38; P < 0.001). Sensitivity, specificity, positive and negative predictive value, and accuracy for LNM detection on 68Ga-PSMA PET/CT in the PLND cohort were 30.6%, 96.5%, 68.8%, 84.5%, and 83.1%, respectively. Undetected LNMs either were micrometastases located in the lymph node border or were without PSMA expression. Conclusion: In this high-risk PCa cohort, we identified advanced disease in about one third at diagnosis. ISUP grade was the superior predictor for advanced disease at diagnosis. We found a significant difference in frequency of advanced disease between ISUP grades 2 and 3, as supports the Gleason score 7 subdivision. Interestingly, we observed no significant differences in risk of advanced disease when comparing the different cT2 stages. The undetected LNMs were either PSMA-negative or micrometastases.

No Added Value of 18F-Sodium Fluoride PET/CT for the Detection of Bone Metastases in Patients with Newly Diagnosed Prostate Cancer with Normal Bone Scintigraphy.

The aim of this study was to determine if additional 18F-sodium fluoride PET/CT (NaF PET/CT) improves the prognostic accuracy in the initial staging of prostate cancer patients with normal bone scintigraphy undergoing prostatectomy. Methods: A prospective cohort study examined NaF PET/CT in intermediate- or high-risk prostate cancer with negative bone scintigraphy who were scheduled for prostatectomy. Biochemical response: PSA levels < 0.2 ng/mL at 6 wk and 6 mo postoperatively, PSA level ≥ 0.2 ng/mL was biochemical failure. Results: Eighty-one patients were included in the study; 75 patients (93%) achieved biochemical responses, 6 patients had biochemical failure. NaF PET/CT indicated bone metastasis in 1 patient (1.2%), was equivocal in 7 patients (8.6%), without bone metastases in 73 patients (90.1%). Eight patients with bone metastases or equivocal results on NaF PET/CT exhibited biochemical responses. All patients with biochemical failure had negative NaF PET/CT and bone scintigraphy for bone metastases. Conclusion: NaF PET/CT has no added value for bone staging in intermediate- and high-risk prostate cancer patients with normal bone scintigraphy results undergoing prostatectomy.

Quantitative Tumor Perfusion Imaging with 82Rb PET/CT in Prostate Cancer: Analytic and Clinical Validation.

The aim of this work was to evaluate 82Rb PET/CT as a diagnostic tool for quantitative tumor blood flow (TBF) imaging in prostate cancer (PCa). Study 1 was performed to evaluate 82Rb as a marker of TBF, using 15O-H2O PET as a reference method. Study 2 investigated the ability of 82Rb uptake measurements to differentiate between PCa and normal prostate. Methods: Study 1: 9 PCa patients scheduled for radical prostatectomy were included. Prostate multiparametric MRI and both cardiac and pelvic 15O-H2O PET and 82Rb PET were performed. PET findings were compared with postprostatectomy Gleason grade group (GGG). Study 2: 15 primary high-risk PCa patients and 12 controls without known prostate disease were included in a clinical drug trial (EudraCT 2016-003185-26). 68Ga-prostate-specific membrane antigen PET/CT scans of PCa patients were available. Pelvic 82Rb PET was performed. Results: Study 1: both 82Rb K1 and 82Rb SUVs correlated strongly with 15O-H2O TBF (ρ = 0.95, P < 0.001, and ρ = 0.77, P = 0.015, respectively). 82Rb SUV and K1 were linearly correlated (r = 0.92, P = 0.001). 82Rb SUV correlated with postprostatectomy GGG (ρ = 0.70, P = 0.03). Study 2: 82Rb SUV in PCa (3.19 ± 0.48) was significantly higher than prostate 82Rb SUV in healthy controls (1.68 ± 0.37) (P < 0.001), with no overlap between groups. Conclusion: Study 1 shows that 82Rb PET/CT can be used for TBF quantification and that TBF can be estimated by simple SUV and suggests that 82Rb SUV is associated with postprostatectomy GGG and, hence, cancer aggressiveness. Study 2 shows that 82Rb uptake is significantly higher in PCa than in normal prostate tissue with no overlap between cohorts, confirming the primary hypothesis of the clinical trial. Consequently, 82Rb PET/CT may have potential as a noninvasive tool for evaluation of tumor aggressiveness and monitoring in nonmetastatic PCa.

Diagnostic test accuracy study of 18F-sodium fluoride PET/CT, 99mTc-labelled diphosphonate SPECT/CT, and planar bone scintigraphy for diagnosis of bone metastases in newly diagnosed, high-risk prostate cancer.

The aim of this study was to prospectively compare planar, bone scan (BS) versus SPECT/CT and NaF PET/CT in detecting bone metastases in prostate cancer. Thirty-seven consecutive, newly diagnosed, prostate cancer patients with prostate specific antigen (PSA) levels ≥ 50 ng/mL and who were considered eligible for androgen-deprivation therapy (ADT) were included in this study. BS, SPECT/CT, and NaF PET/CT, were performed prior to treatment and were repeated after six months of ADT. Baseline images from each index test were independently read by two experienced readers. The reference standard was based on a consensus decision made by a multidisciplinary team on the basis of baseline and follow-up images of the index tests, the findings of the baseline index tests by the experienced readers, and any available imaging, biochemical, and clinical data, including the response to ADT. Twenty-seven (73%) of the 37 patients had bone metastases according to the reference standard. The sensitivities for BS, SPECT/CT and NaF PET/CT were 78%, 89%, and 89%, respectively, and the specificities were 90%, 100%, and 90%, respectively. The positive predictive values of BS, SPECT/CT and NaF PET/CT were 96%, 100%, and 96%, respectively, and the negative predictive values were 60%, 77% and 75%, respectively. No statistically significant difference among the three imaging modalities was observed. All three imaging modalities showed high sensitivity and specificity. NaF PET/CT and SPECT/CT showed numerically improved, but not statistically superior, sensitivity compared with BS in this limited and selected patient cohort.