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Simultaneous PET/MRI imaging has the advantage of combining metabolic information from PET with the high-spatial resolution of MRI to identify disease with greater accuracy than conventional imaging. F-18 rhPSMA 7.3 (rhPSMA) ligands are a new class of diagnostic/therapeutic PSMA-targeting agents in prostate cancer (PCa). We hypothesized that F-18 rhPSMA 7.3 PET/MRI accurately detects recurrent PCa to direct field design in salvage radiation therapy (RT) planning even at low PSA levels. This is a prospective phase II pilot study enrolling men with biochemical recurrence (BCR) after prostatectomy for PCa who underwent rhPSMA 7.3 PET on a simultaneous 3T PET/MRI scanner. The radiation oncologists answered surveys to document changes to RT plan based on the PET/MRI results. All patients underwent standard fractionated RT with at least 6 months of hormonal therapy (HR). Patients with positive scan returned 6-18 months after the first scan for a second timepoint PET/MRI scan after treatment. Standard of truth was established by pathology when feasible or a combination of confirmatory imaging showing radiographic and PSA response after treatment. The primary aim is to evaluate the positive predictive value (PPV) of rhPSMA PET/MRI in detecting disease. The secondary aims included change in RT plan after rhPSMA PET/MRI and treatment response. 29 patients with a median age of 66 years (IQR: 47-76) at the time of imaging were enrolled between Aug 2021 to Jan 2023, of which 28 patients underwent rhPSMA PET/MRI scan. The Gleason score at diagnosis was ≥7 with a median PSA of 7.0 ng/mL (IQR: 0.9-29.5) before surgery. Median PSA was 0.3 ng/mL (IQR: 0.2-1.5) at BCR presentation with 24 (86%) patients having PSA <0.5. Twenty patients (71%) had rhPSMA positive findings. 4/20 patients with rhPSMA positive lesions did not receive follow up imaging as they chose to undergo treatment elsewhere. Of the 16 patients who underwent a confirmatory scan and/or biopsy, 15/16 (94%) patients were found to be true positive while 1/16 (6%) was a false positive. RT plan was changed in 22/28 (79%) with major changes including extension of clinical target volumes to cover PSMA positive pelvic lesions or cancellation of RT due to polymetastatic disease in 8/22 (36%), minor changes including dose escalation to gross disease or dose de-escalation to the rest of prostate fossa in 9/22 (41%) and both major and minor changes in 5/22 (23%) patients. All 14 patients who underwent a combination of RT and HT had complete response on the second timepoint rhPSMA PET/MRI. Median PSA was <0.1 ng/mL (IQR: <0.1-0.1) ng/mL after treatment before the second scan. Even at low PSA levels, F-18 rhPSMA 7.3 PET/MRI resulted in a high detection rate of true positive lesions. Furthermore, incorporation of this technology led to changes in 79% of RT plans. Simultaneous F-18 rhPSMA 7.3 PET/MRI imaging can potentially serve as a "one stop shop" to stratify patient treatment and tailor salvage radiation fields. (NCT04978675) [ABSTRACT FROM AUTHOR]

Radiohybrid PET radiopharmaceutical 18F-flotufolastat (18F-rhPSMA-7.3) is a novel high affinity PSMA-targeting ligand. Clinical data show it to have lower average urinary excretion than reported for other renally-cleared PSMA-PET-ligands, suggesting potential for improved lesion detection in the pelvis. The SPOTLIGHT study (NCT04186845) evaluated the performance of 18F-flotufolastat in men with suspected prostate cancer recurrence. Here, we report findings from a post-hoc analysis of SPOTLIGHT to determine 18F-flotufolastat detection rates (DR) in the pelvic region (prostate bed and pelvic lymph nodes [PLN]) of patients previously treated with radical prostatectomy (RP) only, and with a baseline (prior to PET) PSA level <1 ng/mL. The present report analyzed all PSA-recurrent patients previously treated with RP only who had an evaluable scan and a baseline PSA <1 ng/mL. Patients underwent PET 50-70 min after IV administration of 296 MBq 18F-flotufolastat. Scans were evaluated by 3 blinded central readers, with the majority read representing agreement between ?2 readers. Patient-level and pelvic region DR (% positivity of all scans) by majority read were determined, stratifying DR according to patients' baseline PSA. Of the 389 SPOTLIGHT patients with an evaluable 18F-flotufolastat scan, 168 had previously undergone RP only. Of these, 119 had a baseline PSA <1 ng/mL and were eligible for this analysis. In total, 69% (82/119) of patients with a PSA <1 ng/mL and 67% (57/85) with a PSA <0.5 ng/mL had a positive 18F-flotufolastat scan by majority read. As shown in Table 1, at PSA <0.5 ng/mL, the prostate bed DR was 25/85 (29%). However, in 20/85 (24%) patients, recurrence was limited to the prostate bed only. PLN DR was 13/85 (15%), with 6/85 (7.1%) showing recurrence only in PLN. At PSA ?0.5 - <1 ng/mL, the prostate bed DR increased to 14/34 (41%) with the prostate bed only DR remaining at 8/34 (24%). PLN DR also increased to 13/34 (38%), with 6/34 (18%) showing recurrence only in PLN. Among this post-RP cohort of patients with PSA levels <1 ng/mL, 69% had 18F-flotufolastat-avid lesions. Approximately one-third of patients had detectable recurrence in the prostate bed, suggesting 18F-flotufolastat may be a useful tool for identification of recurrence adjacent to bladder, thus providing potential to guide curative salvage therapy in men with early biochemical recurrence of prostate cancer. [ABSTRACT FROM AUTHOR]

There has been increased utilization of metastasis directed therapy (MDT) for oligometastatic prostate cancer. Despite data demonstrating the benefit of upfront hormone therapy (HT) and synergy between radiation and HT, there exists no randomized trials testing their combination. As it is accepted by most clinicians and men with prostate cancer that time off HT holds intrinsic value, we evaluated whether the addition of metastasis directed therapy (MDT) to intermittent HT in men with oligometastatic prostate cancer facilities time off HT by improving PFS and eugonad PFS. EXTEND (NCT03599765) is a phase II randomized basket trial for multiple solid tumors testing whether the addition of MDT improves PFS. The primary endpoint was pre-specified to be independently assessed and reported for the prostate intermittent HT basket at 41 events. Men with ≤5 metastases were randomized after ≥2 months of HT to continuing HT with or without MDT. HT consisted of a luteinizing hormone-releasing hormone agonist/antagonist with or without a 2nd generation androgen-receptor targeting agent (SART). The primary endpoint was progression, defined as death or radiographic, clinical, or biochemical progression. A planned HT break occurred 6 months after enrollment, after which HT was withheld until progression. The study was designed to have 80% power to detect an improvement in median PFS from 18 to 36 months, with a type I error of 0.1. Exploratory analysis included flow cytometry and TCR sequencing from peripheral blood at baseline and 3 months follow up. Between Sept 2018 to Nov 2020, 87 men were randomized, 43 combined therapy and 44 to HT-only. Arms were well balanced. At a median follow-up of 22.1 months (range 13.0 to 39.3 months), 41 events were observed. PFS was improved by the receipt of MDT (median not reached vs 15.8 months for HT-only, P<0.001; HR=0.25 [95% CI, 0.12 to 0.55]). Among secondary endpoints, time from eugonad testosterone levels (>150 ng/dL) to progression was improved by MDT (median not reached vs 6.1 months, P=0.03), as was time to appearance of new lesions (2-year rate 33% vs 41%, P=0.04). Three grade 3 toxicities were observed in each arm. Subgroup analysis identified PFS improvement with MDT in patients who received (HR=0.24 [95% CI, 0.08 to 0.71]) or did not receive a SART (HR=0.36 [95% CI, 0.15 to 0.83]). Flow cytometry and TCR sequencing demonstrated increases in markers of T cell activation, proliferation, and clonal expansion limited to the combined therapy arm. EXTEND represents the first randomized study to evaluate MDT with HT in oligometastatic prostate cancer and demonstrated improvement in PFS and eugonad PFS. Combination of MDT with intermittent HT may allow for both excellent disease control while facilitating prolonged eugonad testosterone intervals. [ABSTRACT FROM AUTHOR]

Patients with de novo clinical T4 (cT4) prostate cancer represent a heterogenous and understudied population. The advanced nature of their local disease often results in obstructive urinary symptoms that lead to significant morbidity and mortality. We analyzed the effects of definitive local therapy on the outcomes of patients with cT4 prostate cancer. We retrospectively reviewed 155 patients with de novo cT4 prostate cancer, treated at a single institution between 1996 and 2020. Baseline obstructive symptoms were defined as lower urinary tract symptoms (LUTS, AUA_SI>20 on flomax), urinary retention requiring foley, or acute renal failure (ARF). The association between baseline and treatment characteristics with outcomes were analyzed using Cox regression univariable analysis (UVA) and multivariable analysis (MVA), p<0.05 was considered significant. Analysis included 155 men, with median follow-up of 71 mos. Most patients had adenocarcinoma (88%), Gleason 9-10 (77%), and median baseline PSA of 19.9ng/ml (range, 0.5-1110). The majority of patients had T4NanyM1 disease (54%), followed by T4N1M0 (24%), and T4N0M0 (22%), as defined by conventional imaging studies. All men received systemic therapy with ADT (80%), ADT+abiraterone (12%), ADT+chemo (4%) or chemotherapy alone (4%). Local therapy was delivered with radiation (RT) (n=44), surgery (n=28), or both (n=9). Median prostate RT dose was 78Gy (IQR, 70-78) in 2Gy fractions. Patients did not receive definitive RT to their metastatic disease. Seventy-two (47%) men presented with obstructive symptoms with 36 (25%) being catheter dependent. For patients with obstructive symptoms, local therapy was associated with improved overall survival (OS: HR 0.33, p=0.001), freedom from local recurrence (FFLR:HR 0.19, p=0.003), and freedom from castration resistance (FFCR:HR 0.28, p=0.002). Patients who received local therapy were less likely to have local progression (HR 0.23, p=0.01), obstructive symptoms with progression (HR 0.21, p=0.03), or die with local disease (HR 0.15, p=0.001). On MVA local therapy improved OS (HR 0.45, p=0.03). OS was also affected by Gleason 10 and M1 disease (HR 15.58, p=0.02, HR 2.99, p=0.004; respectively). Conversely, in men who did not present with obstructive symptoms (n=83), there was no improvement in OS (HR=0.63, P=0.15). Men with cT4 prostate cancer commonly present with obstructive symptoms due to local disease burden, representing a source of significant morbidity and potential mortality. Even among patients with metastatic disease, definitive local therapy is associated with improved patient outcomes including OS. Pending prospective evaluation, these data support the use of local therapy in men with cT4 disease presenting with obstructive urinary symptoms, irrespective of the presence of metastatic disease. [ABSTRACT FROM AUTHOR]