Citations

Abstract Purpose: DROSHA, DGCR8, and DICER1 regulate miRNA biogenesis and are commonly mutated in cancer. Although DGCR8 and DICER1 germline pathogenic variants (GPV) cause autosomal dominant tumor predisposition, no association between DROSHA GPVs and clinical phenotypes has been reported. Experimental Design: After obtaining informed consent, sequencing was performed on germline and tumor samples from all patients. The occurrence of germline DROSHA GPVs was investigated in large pediatric and adult cancer datasets. The population prevalence of DROSHA GPVs was investigated in the UK Biobank and Geisinger DiscovEHR cohorts. Results: We describe nine children from eight families with heterozygous DROSHA GPVs and a diagnosis of pineoblastoma (n = 8) or Wilms tumor (n = 1). A somatic second hit in DROSHA was detected in all eight tumors analyzed. All pineoblastoma tumors analyzed were classified as miRNA processing–altered 1 subtype. We estimate the population prevalence of germline DROSHA loss-of-function variants to be 1:3,875 to 1:4,843 but find no evidence for increased adult cancer risk. Conclusions: This is the first report of DROSHA-related tumor predisposition. As pineoblastoma and Wilms tumor are also associated with DICER1 GPVs, our results suggest that the tissues of origin for these tumors are uniquely tolerant of general miRNA loss. The miRNA processing–altered 1 pineoblastoma subtype is associated with older age of diagnosis and better outcomes than other subtypes, suggesting DROSHA GPV status may have important clinical and prognostic significance. We suggest that genetic testing for DROSHA GPVs be considered for patients with pineoblastoma, Wilms tumor, or other DICER1-/DGCR8-related conditions and propose surveillance recommendations through research studies for individuals with DROSHA GPVs.

BACKGROUND: Patients with arrhythmogenic mitral valve prolapse syndrome are at increased risk for life-threatening ventricular arrhythmias, but studies have been limited by small sample sizes. We sought to assemble an international arrhythmogenic mitral valve prolapse syndrome registry to delineate the clinical, imaging, and treatment characteristics of patients with arrhythmogenic mitral valve prolapse syndrome who survived sudden cardiac arrest (SCA) or had sustained ventricular tachycardia (VT) or ventricular fibrillation. METHODS: In this descriptive registry, we characterized patients with arrhythmogenic mitral valve prolapse syndrome who survived SCA, sustained VT, or ventricular fibrillation. Deidentified data were abstracted locally and combined centrally. RESULTS: We included 148 patients who had SCA or VT/ventricular fibrillation. Patients had a mean age of 43.7±15.4 years; 68% were women, 73% had bileaflet prolapse, 65% had mitral annular disjunction, 67% had nonsustained VT, and 59% had inferolateral T-wave inversions. Syncope (n=54, 48%) and anterolateral T-wave inversion (n=26, 22%) were relatively common. Catheter ablation was performed in 50 (35%) patients for premature ventricular complexes and in 18 (17.7%) patients for VT. Sites of origin for arrhythmias were commonly in the papillary muscles, fascicles, mitral annulus, and inferior/inferolateral left ventricle. CONCLUSIONS: In this international descriptive registry of patients with arrhythmogenic mitral valve prolapse syndrome and SCA, patients were young, women, and had bileaflet mitral valve prolapse, mitral annular disjunction, inferolateral T-wave inversions, and nonsustained VT. A history of syncope and anterolateral T-wave inversions was relatively common in patients who survived SCA or sustained VT/ventricular fibrillation.

387 Background: Level 1 evidence supports treatment of high-risk and node positive PCa using 4-9 weeks of radiotherapy (RT) combined with 18-36 months of androgen deprivation therapy (ADT) with or without abiraterone acetate plus prednisone (AAP). While effective, some cancers recur, and this prolonged treatment is associated with inconvenience and variable morbidity. We aimed to determine whether the biological synergy of stereotactic body radiotherapy (SBRT) with a 6-month combination of ADT, AAP, and the PARP inhibitor niraparib, could enable a shorter intensified, yet safe and effective, therapeutic alternative. Methods: ASCLEPIuS (NCT04194554) is a multicenter investigator-initiated phase I/II trial in high-risk or node positive, homologous recombination unselected, PCa. Patients received 6 months of ADT, AAP, niraparib and SBRT to the prostate (37.5-40 Gy) +/- pelvic lymph nodes (25 Gy). Focal prostate/nodal boosting was permitted. The phase I primary endpoint was the maximum tolerated dose (MTD) of niraparib using the time-to-event continuous reassessment method (3 dose levels: 100 mg and 200 mg held during SBRT, or 200 mg concurrent with SBRT). Dose limiting toxicities (DLT) were any persistent grade 4+ hematologic toxicity or any grade 3+ rectal/urinary toxicity at least possibly related to treatment as assessed by CTCAE v5.0. Patient reported quality of life (QOL) was assessed with the EPIC-26 short form. Linear mixed models were used to compare scores over time. Results: Accrual began in Nov. 2020 with a transition from phase I to phase II in May 2023 after enrolling 54 men. Median follow-up of the phase I cohort is 12.1 months (IQR 9.4-18.9), 80% (n=43) had Grade Group 4-5, median PSA was 17 ng/mL (range, 1-73), 15% (n=8) had cN+ disease, and 76% (n=41) received nodal RT. There were 0 DLTs to date, no grade 3+ rectal or urinary toxicities, and 5 serious adverse events at least possibly attributable to study treatment (anemia, non-rectal gastrointestinal, syncope, infection, musculoskeletal). The most common grade 3 toxicities were hypertension (n = 11, 21%) and leukopenia (n=6, 11%). Transient dose reductions or holds of AAP or niraparib occurred in 10 and 11 patients, respectively. There were no statistically significant declines in patient reported urinary QOL at 6- or 12-months post-treatment compared to baseline (all p >0.15). A transient decline in bowel QOL at 6-months occurred (p<0.01), which improved by 12-months (p=0.16). Conclusions: Our phase I findings support the short-term safety and tolerability of the combination of SBRT to the prostate and nodes, ADT, AAP, and niraparib at an MTD of 200 mg in men with high-risk or node positive PCa. Our trial completed phase II enrollment in May 2024, and longer-term safety, efficacy, and genomic correlations will be presented in the future. Clinical trial information: NCT04194554 .

61 Background: 177 Lu-PSMA-617 was approved in March 2022 for patients with mCRPC pretreated with an androgen receptor pathway inhibitor (ARPI) and a taxane. There are limited data on the effectiveness of treatments post- 177 Lu-PSMA-617. The aim of this study was to describe prostate-specific antigen (PSA) responses among patients with mCRPC receiving a guideline-recommended therapy as the next therapy after 177 Lu-PSMA-617 treatment. Methods: This retrospective, observational study used real-world data from the PRECISION data platform, a proprietary dataset developed by Novartis, comprised of patient-level electronic health record and claims data that represent the US advanced prostate cancer population in the community, academic, urology, and medical oncology settings. Patients with mCRPC who received any guideline-recommended therapy at least 14 days after treatment with 177 Lu-PSMA-617 between March 23, 2022 and July 31, 2024 were included. Guideline-recommended therapies included abiraterone, enzalutamide, darolutamide, apalutamide, cabazitaxel, docetaxel, pembrolizumab, sipuleucel-T, niraparib, olaparib, talazoparib, rucaparib, and radium-223. Patients’ PSA values while on 177 Lu-PSMA-617 treatment were compared with their PSA values during the subsequent therapy course. Proportions of patients achieving reductions in PSA levels ≥50% (PSA50) and ≥80% (PSA80) were estimated. All analyses were descriptive. Results: A total of 152 patients receiving any subsequent guideline-recommended therapy after 177 Lu-PSMA-617 were identified. Mean age was 72.1 years. Most patients received an ARPI (n=93, 61.2%) – abiraterone (n=38), enzalutamide (n=37), darolutamide (n=10), or apalutamide (n=8) – as their subsequent therapy. Of patients who received a taxane (n=42, 27.6%), 24 received cabazitaxel and 18 received docetaxel. Median time to initiation of subsequent therapy was 206 days (interquartile range [IQR] 101–301 days) from 177 Lu-PSMA-617 initiation and 44 days (IQR 17–119 days) from 177 Lu-PSMA-617 discontinuation. Overall, among patients with sufficient information for PSA evaluation (n=30), 46.7% achieved PSA50 and 40.0% PSA80 post- 177 Lu-PSMA-617. Among patients receiving an ARPI, PSA50 was observed in 11/18 (61.1%) and PSA80 in 10/18 (55.6%). Among patients receiving a taxane, PSA50 and PSA80 were seen in 3/12 (25.0%) and 2/12 (16.7%), respectively. Conclusions: In this real-world analysis, the majority of patients who received guideline-recommended therapies after 177 Lu-PSMA-617 achieved at least a PSA50 response, suggesting that 177 Lu-PSMA-617 treatment does not preclude response to other subsequent therapies.

59 Background: There are several real-world data sources for prostate cancer (PC), each with its own limitations; the most notable limitation is an incomplete picture of the multidisciplinary clinical management of PC. The PRECISION data platform, the largest, most comprehensive, and continually updated real-world evidence source on patients with advanced PC to date, tries to address this limitation and shed light on PC management in both urology and oncology practices in both academic and community settings in the US. The platform includes a wide variety of PC-specific data variables among patients with metastatic hormone-sensitive PC (mHSPC) and metastatic castration-resistant PC (mCRPC) treated across the US. This study aims to provide an overview of the characteristics, treatment patterns, and clinical outcomes among patients with mHSPC and mCRPC included in PRECISION to date. Methods: A retrospective cohort study that included patients with a diagnosis of mHSPC or mCRPC (index date) in PRECISION between 2018 and 2024 (cohorts could overlap). For each cohort, patient characteristics and treatment patterns were evaluated descriptively. Results: The PRECISION platform currently includes 72,855 and 33,538 patients with mHSPC and mCRPC, respectively. Among the mHSPC cohort, the mean ± standard deviation (SD) age was 74.5±9.4 years; 67% and 33% were treated at oncology and urology centers, respectively; 40% and 60% were from academic and community settings, respectively. The average ± SD time from mHSPC to mCRPC was 11.2±11.7 months. Overall, 77.6% of patients were treated with androgen-deprivation therapy (ADT), of whom 64.7% had ADT combined with androgen receptor pathway inhibitors (ARPIs) including abiraterone acetate, enzalutamide, and apalutamide. Among the mCRPC cohort, the mean ± SD age was 74.1±9.3 years; similar treatment setting patterns as mHSPC were observed. Overall, 74.6% initiated a first-line (1L) therapy on/after mCRPC diagnosis; 52.1% had 1L ARPIs, 16.2% 1L immunotherapy, and 4.6% 1L taxane chemotherapy. In addition, 2.2% of patients received the recently US FDA-approved therapy, lutetium-177 vipivotide tetraxetan, at some point during their mCRPC disease duration. Conclusions: This analysis provides key insights into the patients included in the PRECISION data platform. This multidisciplinary dataset provides a 70/30 split between oncology and urology centers, and a 40/60 split between academic and community settings. The observed clinical profile, treatment patterns, and outcomes comprise the most comprehensive representation of current treatment practice in the US. Future analyses of clinical outcomes with existing and novel therapies could contribute significantly to our understanding of opportunities to improve the treatment of patients with mHSPC and mCRPC in the US.

56 Background: The broad therapeutic arsenal for mCRPC, with overlapping indications, makes selecting the optimal treatment sequence challenging in clinical practice. The aim of this study was to evaluate the prostate-specific antigen (PSA) responses and overall survival (OS) among patients with mCRPC receiving 177 Lu-PSMA-617 based on prior ARPI and taxane treatment exposure. Methods: This retrospective, observational study used real-world data from the PRECISION data platform, a harmonized dataset of advanced prostate cancer patients in the US from diverse clinical settings. Patients with mCRPC who had received ≥1 dose of 177 Lu-PSMA-617 between March 23, 2022 and July 31, 2024, after prior treatment with ≥1 ARPI and ≥1 taxane, were included. To assess PSA response, the baseline PSA value obtained within 90 days before starting 177 Lu-PSMA-617 was compared with the on-treatment PSA value obtained ≥28 days after 177 Lu-PSMA-617 initiation. The number of patients achieving PSA reductions ≥50% (PSA50) and ≥80% (PSA80) were estimated, with patients classified into two cohorts based on prior ARPI and taxane exposure: (1) prompt cohort: after only 1 ARPI and 1 taxane, and (2) deferred cohort: >1 ARPI and/or >1 taxane. Patient characteristics and treatment patterns were evaluated descriptively. OS from 177 Lu-PSMA-617 initiation was estimated using Kaplan–Meier methodology. Results: A total of 431 patients were included: 177 patients in the prompt cohort and 254 patients in the deferred cohort. Of patients in the deferred cohort, 185 (72.8%) received ≥1 ARPI and 1 taxane, 32 (12.6%) received 1 ARPI and ≥1 taxane, and 37 (14.6%) received ≥1 ARPI and ≥1 taxane. Median (interquartile range age was 73 (67–78) years and most demographic characteristics were balanced between groups. Patients in the deferred cohort had higher median PSA levels at baseline (63.1 ng/mL vs 25.2 ng/mL). PSA50 was observed in 18/33 (55%) patients in the prompt cohort vs 28/66 (42%) in the deferred cohort. PSA80 was observed in 13/33 (39%) patients in the prompt cohort vs 21/66 (31%) in the deferred cohort. Across both cohorts, median OS was 18.0 months (95% confidence interval [CI]: 15.1 months–not reached [NR]). Median OS was NR in patients in the prompt cohort vs 15.1 months in patients in the deferred cohort (95% CI: 11.6 months–NR). Conclusions: In this large real-world study, prompt initiation of 177 Lu-PSMA-617 (after only 1 ARPI and 1 taxane) showed superior clinical outcomes versus deferred initiation of 177 Lu-PSMA-617. Patients were more likely to achieve a PSA reduction ≥50% and ≥80% and had longer OS with prompt initiation of 177 Lu-PSMA-617. These results may help to guide treatment sequencing in clinical practice.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &amp;lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR &amp;lt;1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923

Importance The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; &amp;lt;1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration ClinicalTrials.gov Identifier: NCT04297683