Citations

75 Background: The Rx landscape of pts with mCRPC has recently evolved with the approval of lutetium-177-PSMA-617 (Lu-177) and poly(ADP) ribose polymerase inhibitors (PARPi) either as single agents or as combinations with an androgen receptor pathway inhibitor (ARPI) [PMID: 37442702]. However, real-world data on the uptake of these agents are lacking. Herein, we sought to assess the Rx patterns and attrition rates of pts with mCRPC in the era of newly approved therapies. Methods: The de-identified nationwide Flatiron Health Electronic-Health Record (EHR)-derived database was used to extract pt-level data. Eligibility criteria: diagnosis of mCRPC and Rx line (L) information. The data cut-off date was 5/31/2024. Rx patterns in each line of therapies were summarized using frequency and percentages. All analysis was done using R version 4.2.3. Results: Of the overall cohort of 24,105 pts with metastatic prostate cancer, 12,333 pts diagnosed with mCRPC between 1/1/2013 and 5/9/2024 met the eligibility criteria and were included. Rx trends are summarized (Table). Of pts receiving 1L Rx, 61% of pts received 2L therapy, and 35% received 3L therapy. Androgen receptor pathway inhibitor (ARPI) was the most common Rx in the 1L setting (73.7%), followed by taxane (10%) and sipuleucel-T (3.8%). In 2L, ARPI was again the most frequent Rx (46.8%), followed by taxane (23.6%). In 3L, taxane became the most frequent Rx (35.4%), followed by ARPI (26.2%) and radium-223 (4.9%). Rx trends per year will be presented in the meeting. Conclusions: In the current era,a high proportion of pts with mCRPC receiving 1L Rx do not receive a subsequent line of Rx (39% of pts do not receive 2L, and 65% do not receive 3L Rx). ARPIs and taxanes remain the most frequently used Rx options in most L of therapy. These findings highlight the need for better tolerated Rx, therapies with a novel mechanism of action, and improved access to care for our pts. Rx trends per year will be presented in the meeting. Rx patterns in pts with mCRPC. Rx 1L, n (%)N = 12,333 2L, n (%)N = 7475 3L, n (%)N = 4316 4L, n (%)N = 2339 5L, n (%)N = 1225 ARPI 9085 (73.7) 3503 (46.8) 1130 (26.2) 356 (15.2) 157 (12.8) PARPi-based therapies 93 (0.8) 185 (2.5) 142 (3.3) 98 (4.2) 47 (3.9) Platinum-based therapy 127 (1) 216 (2.9) 198 (4.6) 148 (6.3) 130 (10.6) Lu-177-based therapies 50 (0.4) 109 (1.5) 169 (3.9) 143 (6.3) 103 (8.4) Radium-223 183 (1.5) 241 (3.2) 213 (4.9) 125 (5.3) 79 (6.4) Sipuleucel-T 474 (3.8) 94 (1.3) 53 (1.2) 18 (0.8) 8 (0.7) Taxane 1240 (10) 1763 (23.6) 1526 (35.4) 935 (40) 393 (32) Pembrolizumab 24 (0.2) 41 (0.5) 36 (0.8) 27 (1.2) 29 (2.4) Other*/not-applicable** 665 (5.4)/392 (3.2) 1000 (13.4)/323 (4.3) 602 (14)/247 (5.7) 320 (13.7)/169 (7.2) 162 (13.3)/117 (9.5) *Includes drugs approved for mCRPC in combination with unapproved agents or clinical trial drugs. **Includes agents not approved for prostate cancer.

95 Background: Most pts with prostate cancer with bone metastasis experience symptomatic skeletal events (SSEs) [PMID: 23884473], leading to increased morbidity and mortality. BMAs have been approved since 2007 and are recommended in mCRPC to prevent SSEs in pts with bone metastases or a high risk of osteoporotic fracture. Herein, we sought to assess the real-world trends of BMA administration in pts with mCRPC. Methods: We used the de-identified nationwide Flatiron Health electronic health record (EHR)-derived database to extract pt-level data. Inclusion criteria: pts with mCRPC with available date of diagnosis of mCRPC and information on receipt of BMA. Pts were categorized into 2 cohorts based on BMA receipt (e.g., bisphosphonates, denosumab, teriparatide, romosozumab) or not. Treatment trends of BMA by year of mCRPC diagnosis were summarized using frequency and percentages. Baseline characteristics at the time of mCRPC diagnosis (age, race-ethnicity, practice type, insurance) were compared between cohorts using the Wilcoxon rank-sum and Chi-squared tests. Results: Of 24,105 pts with metastatic prostate cancer in the dataset, 14,112 with mCRPC were eligible and included. 7,990 (56.6%) received BMA while 6,122 (43.4%) did not. In BMA receipt cohort: median age was 75 (IQR 67 – 81), majority were White (61%), treated in community practice (87%) and had commercial health plan (80%). In BMA non receipt cohort: median age was 75 (IQR 68 – 82), majority were White (61%), treated in a community practice (78%), and had commercial health plan (76%). The use of BMA decreased over time from 56% in 2013 to 46% in 2024 (Table). Statistically significant differences existed between cohorts in race-ethnicity, practice type, and insurance (p < 0.001) and will be presented at the meeting. Conclusions: Despite recommendations to use BMAs in pts with mCRPC and bone metastasis or high risk of osteoporotic fracture, our findings reveal a low utilization rate of BMAs in mCRPC setting with a notable decline over time. This highlights the need to incorporate the use of BMAs in clinical practice and improve access to these agents. Trends by year of mCRPC diagnosis in receipt of the first BMA and frequency and percentage of each agent. Year 2013N = 549 2014N = 1035 2015N = 1223 2016N = 1345 2017N = 1441 2018N = 1346 2019N = 1469 2020N = 1380 2021N = 1352 2022N = 1393 2023N = 1196 2024N = 383 Receipt of BMA, n (%) 316 (56) 674 (65) 792 (65) 837 (62) 886 (61) 766 (57) 816 (56) 766 (56) 692 (51) 713 (51) 556 (46) 176 (46) Denosumab, n (%) 190 (60.1) 450 (66.8) 557 (70.3) 599 (71.6) 606 (68.4) 533 (70) 526 (64.5) 488 (63.7) 410 (59.2) 414 (58.1) 290 (52.2) 94 (53) Zoledronic acid, n (%) 120 (38) 220 (32.6) 228 (28.7) 233 (27.8) 270 (30.5) 225 (29) 281 (34.4) 273 (35.6) 277 (40) 295 (41.4) 258 (46.4) 82 (47) Teriparatide, other bisphosphonates, n (%) 6 (1.9) 4 (0.6) 7 (1) 5 (0.6) 10 (1.1) 8 (1) 9 (1.1) 5 (0.7) 5 (0.7) 4 (0.5) 8 (1.4) 0

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation (“watch and wait”) may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

Abstract Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal monocyte-derived dendritic cells or macrophages in Langerhans Cell (LCH) and non-Langerhans (non-LCH) histiocytoses, respectively. The discovery of the BRAF V600E mutation in ~50% of patients with LCH and the non-LCH Erdheim-Chester Disease (ECD) provided the first molecular target in these patients and novel insights into the pathogenesis of these disorders. However, recurrent mutations in the majority of the ~50% of BRAF V600E-wild type patients with non-LCH are unknown. Moreover, recurrent mutations outside of the MAP kinase pathway are undefined throughout histiocytic neoplasms. To address these issues, we performed whole exome sequencing (WES) of frozen biopsies from 24 patients with LCH (n=10) or ECD (n=14) paired with peripheral blood mononuclear cells. 13/24 patients also underwent RNA sequencing (RNA-seq). All mutations in activating kinases were validated by droplet-digital PCR, while targeted-capture next-generation sequencing validated all others. Both adult (n=18; n=2 with LCH) and pediatric cases (n=9; n=8 with LCH) were included. Using combined WES/RNA-seq, activating kinase alterations were identified in 100% of patients. In LCH, 60% and 40% had BRAF V600E and MAP2K1 mutations, respectively. In non-LCH 51%, 14%, 14%, and 7% were BRAFV600E, ARAF, MAP2K1, and NRAS mutant (Fig1A). Overall, a mean of 7 non-synonymous mutations per adult patient was identified (range 1-22) compared with 5 mutations per pediatric patient (range 4-9; p =ns). Mutations affecting diverse cellular processes were found to co-exist with kinase mutations including mutations in epigenetic modifiers and the p38/MAPK pathway. In addition to kinase point mutations, RNA-seq identified recurrent, in-frame kinase fusions-a first for these disorders. All identified fusions were validated using FISH and RT-PCR. This includes novel fusions in BRAF (RNF11-BRAF and CLIP2-BRAF), as well as therapeutically important fusions in ALK (2 separate KIF5B-ALK fusions) and NTRK1 (LMNA-NTRK1;Fig1B). Expression of each fusion in Ba/F3 cells conferred cytokine-independent growth. Importantly, the BRAF fusions were found to be sensitive to MEK inhibition but resistant to vemurafenib while the ALK fusions conferred sensitivity to the ALK inhibitors crizotinib or alectinib. We next interrogated a validation cohort of 37 BRAF V600E-wild type, non-LCH, formalin-fixed, paraffin-embedded tissue samples using targeted mutational profiling for MAP2K1, ARAF, NRAS, KRAS, and PIK3CA. This revealed activating mutations in MAP2K1 (32%; n=12), NRAS (16%; n=6), KRAS (11%; n=4), PIK3CA (8%; n=3), and ARAF (3%; n=1). Three of the investigated non-LCH patients with refractory disease and progressive organ dysfunction were treated with targeted therapies based on the discovery of novel kinase alterations described above. Treatment of 2 refractory MAP2K1- mutant, non-LCH patients with MEK inhibitors (trametinib or cobimetinib) resulted in dramatic clinical improvement (Fig1C). Both patients have been maintained on MEK inhibitor single-agent therapy with a sustained clinical response for >100 days. Further evidence of effective targeted inhibition was found in a refractory ECD patient carrying an ARAF S214A mutation. This patient failed to respond to 3 lines of prior therapies and suffered near blindness due to disease infiltration in the retina and optic nerves. Given a recent report of complete response to sorafenib in a lung cancer patient with an ARAF S214C mutation, we initiated sorafenib. Within 12 weeks, there was improvement in the patientÕs eyesight and decreased infiltrative disease, coinciding with >50% decrease in mutant ARAF DNA in plasma cell-free DNA. Whole exome and transcriptome sequencing identified activating kinase mutations or translocations in all patients with the common downstream effect of activating the MAPK pathway. The preliminary, dramatic, clinical efficacy observed with use of MEK and RAF inhibitors in MAP2K1 - and ARAF-mutated, non-LCH patients further supports the central role of targeting the MAPK pathway in these tumors. The discovery of the discussed mutations and fusions in diverse kinases provides critical new insights into the genetic events central to a spectrum of adult and pediatric histiocytic neoplasms. Figure 1. Figure 1. Disclosures Off Label Use: This abstract describes use of MEK inhibitors (both tremetinib and cobimetinib) as well as sorafenib for MEK1 and ARAF mutant histiocytosis. . Stephens:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine, Inc.: Employment, Equity Ownership. Ross:Foundation Medicine Inc.: Employment. Ali:Foundation Medicine Inc.: Employment. Hyman:Chugai Pharma: Consultancy; Biotherapeutics: Consultancy; Atara: Consultancy, Honoraria.

Abstract Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAFV600E mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAFV600E–wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAFV600E–wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. Significance: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders. Cancer Discov; 6(2); 154–65. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109