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.
<div>AbstractPurpose:<p>Enzalutamide after abiraterone progression is commonly used in metastatic castration-resistant prostate cancer despite a low rate of clinical benefit. Analyzing IMbassador250, a phase III trial assessing enzalutamide with or without atezolizumab after abiraterone, we hypothesized that baseline and early changes in circulating tumor DNA (ctDNA) tumor fraction (TF) may identify patients more likely to exhibit survival benefit from enzalutamide.</p>Experimental Design:<p>ctDNA was quantified from plasma samples using a tissue-agnostic assay without buffy coat sequencing. Baseline ctDNA TF, changes in ctDNA TF from baseline to cycle 3 day 1 (C3D1), and detection at C3D1 alone were compared with overall response rate, radiographic progression-free survival (rPFS), median OS (mOS), and 50% reduction in PSA.</p>Results:<p>ctDNA TF detection at baseline and/or C3D1 was associated with shorter rPFS and OS in 494 evaluable patients. Detection of ctDNA TF at C3D1, with or without detection at cycle 1 day 1, was associated with worse rPFS and mOS than lack of detection. When ctDNA TF and PSA response at C3D1 were discordant, patients with (ctDNA TF undetected/PSA not reduced) had more favorable outcomes than (ctDNA TF detected/PSA reduced; mOS 22.1 vs. 16 months; <i>P</i> < 0.001).</p>Conclusions:<p>In a large cohort of patients with metastatic castration-resistant prostate cancer receiving enzalutamide after abiraterone, we demonstrate the utility of a new tissue-agnostic assay for monitoring molecular response based on ctDNA TF detection and dynamics. ctDNA TF provides a minimally invasive, complementary biomarker to PSA testing and may refine personalized treatment approaches.</p></div>
621 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is projected to be the 3 rd leading cause of cancer related death in the United States in 2023. Most patients are diagnosed at an advanced/metastatic stage and 5-year survival remains dismal at ~12%. While effective regimens are limited, some patients benefit significantly from chemotherapy, while others harbor disease that progresses despite treatment. Unfortunately, it is impossible to predict individual patient outcomes on treatment such that only general prognostic information can be provided to patients and families. Quantification of circulating tumor DNA (ctDNA) is a promising prognostic biomarker and emerging evidence shows that baseline ctDNA tumor fraction (TF) is prognostic in several tumor types. This study represents the largest data set reported to date aimed at evaluating the prognostic value of ctDNA TF in metastatic PDAC (mPDAC). Methods: This study used a cohort of patients from the de-identified nationwide Flatiron Health-Foundation Medicine pancreatic clinico-genomic database who underwent ctDNA testing using FoundationOne Liquid or FoundationOne Liquid CDx as part of routine care. Data originated from approximately 280 US cancer clinics. Patient/disease characteristics, laboratory and treatment data were captured from the electronic health record. Real-world overall survival (rwOS) and time-to-next-treatment (rwTTNT) were evaluated by ctDNA TF while controlling for relevant covariates. In parallel analyses, ctDNA TF cutoffs of ≥1% and ≥10% were evaluated. Exploratory analysis of trichotomized ctDNA TF at 1% and 10% was also performed. Results: 290 patients with mPDAC were included. High ctDNA TF was associated with poor prognostic clinical features regardless of cutpoint. High ctDNA TF also correlated with significantly reduced rwOS in univariable analysis and after correction for covariates, regardless of cutpoint (1%: adj HR 1.33 [0.93-1.90], adj P = 0.12; 10%: adj HR 1.91 [1.28-2.87], adj P = 0.002). The same was observed for rwTTNT (1%: adj HR 1.59 [1.14-2.22], adj P = 0.006; 10%: adj HR 2.18 [1.49-3.19], adj P < 0.001). When ctDNA TF was trichotomized, higher ctDNA TF groups had reduced rwOS and rwTTNT in a stepwise manner in univariable analysis and after correction for covariates (all vs <1%; rwOS: adj HR for 1%-<10% 1.06 [0.71-1.59], adj P = 0.78; adj HR for ≥10% 1.97 [1.26-3.09], adj P = 0.003; rwTTNT: adj HR for 1%-<10% 1.26 [0.87-1.84], adj P = 0.22; adj HR for ≥10% 2.43 [1.60-3.70], adj P < 0.001). Conclusions: ctDNA TF is a prognostic biomarker in mPDAC with potential to inform expected longevity of patients. Uniform cohorts, with regard to treatments given and line of therapy, would help further evaluate the ability of ctDNA TF to identify patients with aggressive disease and inform the design of future studies to personalize therapeutic decision-making.
<p>2nd line treatment-TMB interaction models from Figure 2. The (A) TTNT and (B) OS interaction models are shown for for propensity adjusted analyses in Figure 2.</p>
<div>AbstractPurpose:<p>Alpelisib is a PI3K alpha (PI3Kα)-selective inhibitor approved for the treatment of hormone receptor–positive/HER2-negative (HR<sup>+</sup>/HER2<sup>−</sup>) <i>PIK3CA</i>-mutated advanced breast cancer (ABC) based on the SOLAR-1 trial, which defined 11 substitutions in exons 7, 9, and 20 in <i>PIK3CA</i> (SOLAR1m). We report alpelisib effectiveness for ABC harboring SOLAR1m, as well as other pathogenic <i>PIK3CA</i> mutations (OTHERm) using comprehensive genomic profiling (CGP).</p>Experimental Design:<p>A total of 33,977 tissue and 1,587 liquid biopsies were analyzed using hybrid capture–based CGP covering the entire coding sequence of <i>PIK3CA</i>. Clinical characteristics and treatment history were available for 10,750 patients with ABC in the deidentified Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB).</p>Results:<p><i>PIK3CA</i>m were detected in 11,767/33,977 (35%) of tissue biopsies, including 2,300 (7%) samples with OTHERm and no SOLAR1m. Liquid biopsy had 77% sensitivity detecting <i>PIK3CA</i>m, increasing to 95% with circulating tumor DNA fraction ≥2%. In patients with HR<sup>+</sup>/HER2<sup>−</sup> ABC and <i>PIK3CA</i>m receiving alpelisib/fulvestrant (ALP+FUL; <i>n</i> = 182) or fulvestrant alone (FUL; <i>n</i> = 119), median real-world progression-free survival (rwPFS) was 5.9 months on ALP+FUL [95% confidence interval (CI): 5.1–7.4] versus 3.1 months on FUL (95% CI: 2.7–3.7; <i>P</i> < 0.0001). In patients with OTHERm, median rwPFS was 4.0 months on ALP+FUL (95% CI: 2.8–10.1) versus 2.5 months on FUL (95% CI: 2.2–3.7; <i>P</i> = 0.0054).</p>Conclusions:<p>CGP detects diverse <i>PIK3CA</i>m in a greater number of patients with ABC than PCR hotspot testing; 20% of patients with <i>PIK3CA</i>m do not have SOLAR1m. These patients may derive benefit from alpelisib.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-22-3411" target="_blank">See related commentary by Tau and Miller, p. 989</a></i></p></div>
