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The role of prostate-specific membrane antigen (PSMA)-targeted PET in comparison to multiparametric MRI (mpMRI) in the evaluation of intraprostatic cancer foci is not well defined. The aim of our study was to compare the diagnostic performance of 68Ga-PSMA-11 PET/CT (PSMA PET/CT), mpMRI, and PSMA PET/CT + mpMRI using 3 independent masked readers for each modality and with histopathology as the gold standard in the detection, intraprostatic localization, and determination of local extension of primary prostate cancer. Methods: Patients with intermediate- or high-risk prostate cancer who underwent PSMA PET/CT as part of a prospective trial (NCT03368547) and mpMRI before radical prostatectomy were included. Each imaging modality was interpreted by 3 independent readers who were unaware of the other modality result. A central majority rule was applied (2:1). Pathologic examination of whole-mount slices was used as the gold standard. Imaging scans and whole-mount slices were interpreted using the same standardized approach on a segment level and a lesion level. A "neighboring" approach was used to define imaging-pathology correlation for the detection of individual prostate cancer foci. Accuracy in determining the location, extraprostatic extension (EPE), and seminal vesicle invasion (SVI) of prostate cancer foci was assessed using receiver-operating-characteristic curve analysis. Interreader agreement was calculated using intraclass correlation coefficient analysis. Results: The final analysis included 74 patients (14 [19%] with intermediate risk and 60 [81%] with high risk). The cancer detection rate (lesion-based analysis) was 85%, 83%, and 87% for PSMA PET/CT, mpMRI, and PSMA PET/CT + mpMRI, respectively. The change in AUC was statistically significant between PSMA PET/CT + mpMRI and the 2 imaging modalities alone for delineation of tumor localization (segment-based analysis) (P < 0.001) but not between PSMA PET/CT and mpMRI (P = 0.093). mpMRI outperformed PSMA PET/CT in detecting EPE (P = 0.002) and SVI (P = 0.001). In the segment-level analysis, intraclass correlation coefficient analysis showed moderate reliability among PSMA PET/CT and mpMRI readers using a 5-point Likert scale (range, 0.53-0.64). In the evaluation of T staging, poor reliability was found among PSMA PET/CT readers and poor to moderate reliability was found for mpMRI readers. Conclusion: PSMA PET/CT and mpMRI have similar accuracy in the detection and intraprostatic localization of prostate cancer foci. mpMRI performs better in identifying EPE and SVI. For the T-staging evaluation of intermediate to high-risk prostate cancer, mpMRI should still be considered the imaging modality of reference. Whenever available, PSMA PET/MRI or the coregistration or fusion of PSMA PET/CT and mpMRI (PSMA PET/CT + mpMRI) should be used as it improves tumor extent delineation.

Prostate-specific membrane antigen (PSMA) ligand PET induces management changes in patients with prostate cancer. We aim to better characterize the impact of 68Ga-PSMA-11 PET (68Ga-PSMA PET) on management of recurrent prostate cancer in a large prospective cohort. Methods: We report management changes after 68Ga-PSMA PET, a secondary endpoint of a prospective multicenter trial in men with biochemical recurrence of prostate cancer. Pre-PET (Q1), post-PET (Q2), and posttreatment (Q3) questionnaires were sent to referring physicians recording site of recurrence and intended (Q1 to Q2 change) and implemented (Q3) therapeutic and diagnostic management. Results: Q1 and Q2 response was collected for 382 of 635 patients (60%, intended cohort), and Q1, Q2, and Q3 response was collected for 206 patients (32%, implemented cohort). An intended management change occurred in 260 of 382 (68%) patients. The intended change was considered major in 176 of 382 (46%) patients. Major changes occurred most often for patients with prostate-specific antigen of 0.5 to less than 2.0 ng/mL (81/147, 55%). By analysis of stage groups, management change was consistent with PET disease location, that is, a majority of major changes toward active surveillance (47%) for unknown disease site (103/382, 27%), toward local or focal therapy (56%) for locoregional disease (126/382, 33%), and toward systemic therapy (69% M1a; 43% M1b/c) for metastatic disease (153/382, 40%). According to Q3 responses, the intended management was implemented in 160 of 206 (78%) patients. In total, 150 intended diagnostic tests, mostly CT (n = 43, 29%) and bone scans or 18F-NaF PET (n = 52, 35%), were prevented by 68Ga-PSMA PET; 73 tests, mostly biopsies (n = 44, 60%) as requested by the study protocol, were triggered. Conclusion: According to referring physicians, sites of recurrence were clarified by 68Ga-PSMA PET, and disease localization translated into management changes in more than half of patients with biochemical recurrence of prostate cancer.

The impact of prostate-specific membrane antigen (PSMA) PET/CT on management of prostate cancer (PCa) patients with biochemical recurrence (BCR) is well established. However, whether and how PSMA PET/CT affects the management of patients undergoing scans for other clinical indications remains unknown. The goal of this study was to determine the impact of 68Ga-PSMA-11 PET/CT on initial and subsequent management decisions in a cohort of PCa patients referred for various indications (i.e., a basket trial) excluding the 2 main classic indications: BCR and presurgical staging. Methods: This was a prospective study of 197 patients that aimed to determine the impact of 68Ga-PSMA-11 PET/CT on PCa stage and management. The indications for PSMA PET/CT were initial staging of nonsurgical candidates (30 patients) and restaging after definitive treatment (167 patients). The restaging cohort comprised patients restaged with known advanced metastatic disease (n = 103), after androgen deprivation therapy only (n = 16), after surgery and with serum prostate-specific antigen levels lower than 0.2 ng/mL (n = 13), after radiation therapy and not meeting the Phoenix criteria (n = 22), and after other primary local treatments (i.e., high-intensity focused ultrasound, focal laser ablation, cryoablation, hyperthermia, or irreversible electroporation) (n = 13). Patients with BCR and candidates for curative surgery were excluded. Impact on management was assessed using pre- and post-PET questionnaires completed by referring physicians, electronic chart review, or patient telephone calls. Results: PSMA PET/CT changed the disease stage in 135 of 197 (69%) patients (upstaging in 38%, downstaging in 30%, and no change in stage in 32%). Management was affected in 104 of 182 (57%) patients. Specifically, PSMA PET/CT impacted the management of patients who were restaged after radiation therapy without meeting the Phoenix criteria for BCR, after other definitive local treatments, and with advanced metastatic disease in 13 of 18 (72%), 8 of 12 (67%), and 59 of 96 (61%), respectively. Conclusion: PSMA PET/CT has a profound impact on stage and management of PCa patients outside the 2 main classic indications (BCR and presurgical staging) across all examined clinical scenarios.

Standard-of-care imaging for initial staging of prostate cancer (PCa) underestimates disease burden. Prostate-specific membrane antigen (PSMA) PET/CT detects PCa metastasis with superior accuracy, having a potential impact on the planning of definitive radiation therapy (RT) for nonmetastatic PCa. Our objectives were to determine how often definitive RT planning based on standard target volumes covers 68Ga-PSMA-11 PET/CT-defined disease and to assess the potential impact of 68Ga-PSMA-11 PET/CT on definitive RT planning. Methods: This was a post hoc analysis of an intention-to-treat population of 73 patients with localized PCa without prior local therapy who underwent 68Ga-PSMA PET/CT for initial staging as part of an investigational new drug trial. Eleven of the 73 were intermediate-risk (15%), 33 were high-risk (45%), 22 were very-high-risk (30%), and 7 were N1 (9.5%). Clinical target volumes (CTVs), which included the prostate, seminal vesicles, and (in accord with the Radiation Therapy Oncology Group consensus guidelines) pelvic lymph nodes (LNs), were contoured on the CT portion of the PET/CT images by a radiation oncologist masked to the PET findings. 68Ga-PSMA-11 PET/CT images were analyzed by a nuclear medicine physician. 68Ga-PSMA-11-positive lesions not covered by planning volumes based on the CTVs were considered to have a major potential impact on treatment planning. Results: All patients had one or more 68Ga-PSMA-11-positive primary prostate lesions. Twenty-five (34%) and 7 (9.5%) of the 73 patients had 68Ga-PSMA-11-positive pelvic LN and distant metastases, respectively. The sites of LN metastases in decreasing order of frequency were external iliac (20.5%), common iliac (13.5%), internal iliac (12.5%) obturator (12.5%), perirectal (4%), abdominal (4%), upper diaphragm (4%), and presacral (1.5%). The median size of the LN lesions was 6 mm (range, 4-24 mm). RT planning based on the CTVs covered 69 (94.5%) of the 73 primary lesions and 20 (80%) of the 25 pelvic LN lesions, on a per-patient analysis. Conclusion:68Ga-PSMA-11 PET/CT had a major impact on intended definitive RT planning for PCa in 12 (16.5%) of the 73 patients whose RT fields covered the prostate, seminal vesicles, and pelvic LNs and in 25 (37%) of the 66 patients whose RT fields covered the prostate and seminal vesicles but not the pelvic LNs.

To improve prostate-specific membrane antigen (PSMA)-targeted theranostic approaches, robust murine models of prostate cancer are needed. However, important characteristics of preclinical PSMA imaging-that is, the reproducibility of the imaging signal and the relationship between quantitative cell surface PSMA expression and lesion detectability with small-animal PET/CT-have not been defined yet. Methods: Murine prostate cancer RM1 sublines (ras myc transformed cells of C57BL/6 prostate origin) expressing varying levels of human PSMA were injected into the shoulder of C57BL/6 mice on day 0. 68Ga-PSMA11 PET/CT was performed on days 7 and 8 and interpreted by 2 masked readers to determine interday and interreader reproducibility. PSMA expression was quantified on days 7 and 8 by flow cytometry of fine-needle aspiration tumor biopsy samples. Cell surface PSMA expression was correlated with PET signal. The threshold for PET positivity was based on the clinical Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. Results: The maximum and average percentages of injected 68Ga-PSMA11 activity per gram of tissue (%IA/g) correlated nearly perfectly as determined by 2 independent readers and on 2 separate days (intraclass correlation coefficient, 1.00/0.89 and 0.95/0.88, respectively). The number of PSMA molecules per cell increased from the RM1-yellow fluorescent protein subline (PSMA-; 2,000/cell) to the RM1-low subline (PSMA+; 17,000/cell), the RM1-medium subline (PSMA++; 22,000/cell), and the RM1-PGLS subline (PSMA-positive, green fluorescent protein-positive, and luciferase-positive; PSMA+++; 45,000/cell). Expression levels correlated with the visual positivity rate on 68Ga-PSMA11 PET and with the PSMA PET %IA/g. The PSMA threshold for PET positivity was approximately 20,000 per cell. Signal correlation was close at lower PSMA levels (RM1-low to RM1-medium; 10-23 %IA/g) but was lost at higher PSMA levels (RM1-medium to RM1-PGLS; 23-27 %IA/g). Conclusion: The in vivo relationship between 68Ga-PSMA11 PET/CT and PSMA expression level in a murine model of prostate cancer was robust for lower cell surface PSMA expression levels (≤22,000/cell). Thus, preclinical 68Ga-PSMA11 PET/CT can be used as an imaging biomarker to test PSMA-targeted interventions in murine models.

In this prospective survey of referring physicians, we investigated whether and how 68Ga-labeled prostate-specific membrane antigen 11 (68Ga-PSMA-11) PET/CT affects the implemented management of prostate cancer patients with biochemical recurrence (BCR). Methods: We conducted a prospective survey of physicians (NCT02940262) who referred 161 patients with prostate cancer BCR (median prostate-specific antigen value, 1.7 ng/mL; range, 0.05-202 ng/mL). Referring physicians completed one questionnaire before the scan to indicate the treatment plan without 68Ga-PSMA-11 PET/CT information (Q1; n = 101), one immediately after the scan to denote intended management changes (Q2; n = 101), and one 3-6 mo later to document the final implemented management (Q3; n = 56). The implemented management was also obtained via electronic chart review or patient contact (n = 45). Results: A complete documented management strategy (Q1 + Q2 + implemented management) was available for 101 of 161 patients (63%). Seventy-six of these (75%) had a positive 68Ga-PSMA-11 PET/CT result. The implemented management differed from the prescan intended management (Q1) in 54 of 101 patients (53%). The postscan intended management (Q2) differed from the prescan intended management (Q1) in 62 of 101 patients (61%); however, these intended changes were not implemented in 29 of 62 patients (47%). Pelvic nodal and extrapelvic metastatic disease on 68Ga-PSMA-11 PET/CT (PSMA T0N1M0 and PSMA T0N1M1 patterns) was significantly associated with implemented management changes (P = 0.001 and 0.05). Conclusion: Information from 68Ga-PSMA-11 PET/CT brings about management changes in more than 50% of prostate cancer patients with BCR (54/101; 53%). However, intended management changes early after 68Ga-PSMA-11 PET/CT frequently differ from implemented management changes.