Calais, Jeremie

292 Background: Fibroblast activation protein (FAP) has high expression in cancer associated fibroblasts (CAFs) in the tumor microenvironment of many solid tumor malignancies. [ 18 F]FAPI-74 is a fluorine-18 labeled FAP-targeting PET imaging tracer with promising characteristics for detection of malignant disease in a variety of cancers. In this multicenter prospective Phase 2 trial, we hypothesized that [ 18 F]FAPI-74 PET would have a high positive predictive value (PPV) for detecting FAP-expressing tumor tissue in a variety of gastrointestinal (GI) malignancies. Methods: This Phase 2 multicenter trial was conducted in the United States at MGH, MSKCC, BAMF, Northwell, UCLA and Mayo (NCT05641896). Eligible GI cancers in the study included hepatocellular carcinoma, cholangiocarcinoma, gastric, esophageal, pancreatic, and colorectal cancer. Each subject underwent one [ 18 F]FAPI-74 PET scan, and a tissue sample was obtained by biopsy and/or surgical resection. The imaging reads were performed centrally by experienced PET readers. The primary objective was to evaluate the PPV of [ 18 F]FAPI-74 PET in detecting FAP-expressing cells from patient collected tissues using centrally evaluated immunohistochemistry (IHC) with positivity defined by the sponsor as an H score higher than 50. The secondary objective was to evaluate the safety profile of [ 18 F]FAPI-74 and its PPV in detecting the presence of GI malignancies using histopathology as the standard of truth. Results: The trial was activated in May 2023, with the last patient imaged in Jan 2025. Of 103 subjects with GI malignancies, the primary site was gastroesophageal in 46 (45%), pancreatic in 22 (21%), colorectal in 17 (17%), hepatobiliary in 10 (10%) and of other GI origin in 8 (8%) cancers. 60 participants were male and 43 female. In total, 60 patients had viable and representative tissue data for efficacy analysis of primary and secondary endpoints. No serious adverse events were reported because of the investigational product. The PPV of [ 18 F]FAPI-74 PET to detect FAP-expressing cells using IHC was 100% (52/52). The sensitivity and specificity for the detection of FAP were 90% (52/58) and 100% (2/2) respectively. The PPVs of [ 18 F]FAPI-74 PET to detect cancer using histopathology as truth standard was 94% (49/52). The sensitivity for the detection of disease was 91% (49/54). Conclusions: The Phase 2 study in GI cancers demonstrates that [ 18 F]FAPI-74 PET detects FAP expression and presence of disease in cancers of the GI tract. PPV of 100% for primary objective and 94% for secondary objective were determined. These results support initiation of a Phase 3 study of [ 18 F]FAPI-74 PET in patients with GI cancers. In addition, [ 18 F]FAPI-74 PET’s reliability in visualizing FAP expression cells in the tumor microenvironment supports a further role in selection of patients for FAP-directed therapies. Clinical trial information: NCT05641896 .

121 Background: In the Phase 3 VISION trial, treatment with the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) + protocol-permitted standard of care (SoC) significantly improved median radiographic progression-free survival (rPFS; 8.7 vs 3.4 months [mo]) and overall survival (OS; 15.3 vs 11.3 mo) in patients with metastatic castration-resistant prostate cancer (mCRPC) vs SoC alone. However, it is unclear how the addition of androgen receptor pathway inhibitors (ARPIs) affected 177 Lu-PSMA-617 treatment outcomes. Here we compared the efficacy and safety of 177 Lu-PSMA-617 in patients treated with vs without concomitant ARPIs. Methods: In VISION, adult patients with PSMA-positive mCRPC previously treated with ≥1 prior ARPI and 1–2 taxane chemotherapy regimens were randomized 2:1 to receive 177 Lu-PSMA-617 (7.4 GBq Q6W, 4–6 cycles) + SoC (which included ARPIs) vs SoC alone. In this secondary analysis, we assessed baseline characteristics, OS, rPFS, prostate-specific antigen (PSA) response rate, duration of PSA response, PSA-PFS, and safety among patients in the intervention arm who were treated with vs without concomitant ARPIs. Results: In total, 289 patients were treated with concomitant ARPIs and 262 patients were not (N=551). Imbalances between the groups were observed in some baseline characteristics: patients treated with concomitant ARPIs were younger, had lower ECOG performance scores, lower mean PSA and lactate dehydrogenase levels, and fewer prior taxane chemotherapy regimens. Baseline mean standardized [ 68 Ga]Ga-PSMA-11 uptake values and mean hemoglobin levels were well-balanced. A statistically significant difference in median OS was observed in patients treated with concomitant ARPIs vs those without (17.8 vs 12.4 mo; HR, 0.72; 95% CI, 0.58–0.89; nominal P=0.001). No statistically significant between-group differences were observed for rPFS, PSA response rate, duration of PSA response or PSA-PFS. The proportion of adverse events reported was similar in patients with or without concurrent ARPI, except for the number of adverse events leading to interruption of best supportive care/SoC, which was higher in patients treated with concurrent ARPIs. Conclusions: OS was significantly different in patients treated with concomitant ARPIs vs those without, while other efficacy endpoints were not. No new safety signals were observed for 177 Lu-PSMA-617 with concomitant ARPI. These findings may be confounded by varied exposure to ARPIs, or differing patient characteristics; patients who received concomitant ARPIs may represent a more favorable treatment population than those who did not. These findings should be considered as hypothesis-generating, and a multivariate analysis has been planned to ascertain the influence of these potential biases. Clinical trial information: NCT03511664 .

AbstractCurrent US clinical practice guidelines for advanced prostate cancer management contain recommendations based on high‐level evidence from randomized controlled trials; however, these guidelines do not address the nuanced clinical questions that are unanswered by prospective trials but nonetheless encountered in day‐to‐day practice. To address these practical questions, the 2024 US Prostate Cancer Conference (USPCC 2024) was created to generate US‐focused expert clinical decision‐making guidance for circumstances in which level 1 evidence is lacking. At the second annual USPCC meeting (USPCC 2024), a multidisciplinary panel of experts convened to discuss ongoing clinical challenges related to 5 topic areas: biochemical recurrence; metastatic, castration‐sensitive prostate cancer; poly [ADP‐ribose] polymerase inhibitors; prostate‐specific membrane antigen radioligand therapy; and metastatic, castration‐resistant prostate cancer. Through a modified Delphi process, 34 consensus recommendations were developed and are intended to provide clinicians who manage prostate cancer with guidance related to the implementation of novel treatments and technologies. In this report, the authors review the areas of consensus identified by the USPCC 2024 experts and evaluate ongoing unmet needs regarding translational application of the current clinical evidence.

e17061 Background: ThePhase 3 VISION trial demonstrated that [177Lu]Lu-PSMA-617 prolonged overall survival (OS) in metastatic-castration resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor-signaling inhibitors (ARSi). The expanded access program (EAP) (NCT04825652) was opened to provide access to [177Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. The VISION trial required strict inclusion and exclusion criteria, which may not represent the patient population encountered in clinical practice. This study aimed to evaluate the efficacy and safety profile of [177Lu]Lu-PSMA-617 in a real-world setting within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP between May 2021 and March 2022 at four institutions in the United States with available toxicity and outcome data were included. Outcome measures included overall survival (OS), ≥50% PSA decline rates (PSA-RR), and incidences of toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Differences in baseline characteristics, toxicity, and PSA-RR between the EAP and VISION were evaluated using a t-test of proportions. Results: 117 patients with mCRPC were eligible and included. Patients enrolled in the EAP were similarly pretreated with taxane-based chemotherapy regimens (>1 taxane: 47% vs 40%; p=0.16) and more heavily pretreated with ARSi (>1 ARSi: 70% vs 46%; p<0.001). EAP patients had similar levels of ≥3 grade anemia (18% vs 13%; p=0.15), thrombocytopenia (13% vs 8%; p=0.13), and neutropenia (3% vs 3%; p=0.85) and higher levels of ≥3 grade lymphopenia (34% vs 8%; p<0.001). Patients treated within the EAP experienced numerically shorter OS (median OS: 13.7 vs 15.3 months) and similar PSA-RR (40% vs 46%; p=0.29). Median follow-up was numerically shorter in the EAP compared with VISION (14.7 mo vs 20.3 mo). Conclusions: mCRPC patients treated with [177Lu]Lu-PSMA-617 in a real-world setting were more heavily pretreated with ARSi, had a similar safety profile, and experienced numerically shorter OS and similar PSA-RR compared with VISION trial patients. A major limitation of this study is that we did not have access to individual patient data from the VISION trial, so we were not able to assess whether differences in OS between VISION and the EAP were statistically significant.

Background: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. Materials and Methods: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. Results: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)–positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. Conclusions: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

Purpose: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. Materials and Methods: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. Results: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. Conclusions: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.