tbuckley/cabot-search huggingface dataset:
Efficacy of olaparib (O) plus abiraterone (A) versus placebo (P) plus A in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with single homologous recombination repair gene mutations (HRRm) in the PROpel trial.
Authors: Neal D. Shore, Noel Clarke, Andrew J. Armstrong, Mototsugu Oya, Giuseppe Procopio, João Daniel Cardoso Guedes, Cagatay Arslan, Niven Mehra, Emma Brown, Friederike Schlürmann, Jae Young Joung, Mikio Sugimoto, Karina Vianna, Christian Hosius, Alan Barnicle, Yu-Zhen Liu, Elizabeth Harrington, David McGuinness, Paula Michelle del Rosario, Fred Saad
Journal: Journal of Clinical Oncology (2024)

165 Background: PROpel (NCT03732820) met its primary endpoint and showed a significant investigator-assessed radiographic progression-free survival (rPFS) benefit with O + A vs P + A in first-line mCRPC (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P&lt;0.001). At final prespecified analysis, median overall survival (OS) with O + A vs P + A was 42.1 vs 34.7 months (HR 0.81, 95% CI 0.67–1.00; P=0.0544). We report gene-by-gene efficacy of O + A vs P + A for pts from PROpel with a HRRm. Methods: PROpel was a Phase 3 randomized (1:1), double-blind trial. Pts were enrolled irrespective of biomarker status and received O (300 mg twice daily [bid]) or P, plus A (1000 mg once daily) and prednisone/prednisolone (5 mg bid). rPFS by investigator assessment was the primary endpoint (data cutoff [DCO]: 7/30/2021). OS was a key secondary endpoint (DCO: 10/12/2022). Following randomization and before primary analysis, HRRm status was assessed by tumor tissue (FoundationOne CDx) and ctDNA (FoundationOne Liquid CDx) tests and is reported using aggregated results from both tests. Genes assessed were ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. HR and CIs are not reported in subgroups with &lt;5 events in either arm for both rPFS and OS. Results: 28.4% pts had an HRRm.For most pts with a single gene HRRm, there was a lower proportion of rPFS events and deaths in the O + A arm relative to the P + A arm (Table). The most prevalent gene mutations were BRCA2, ATM and CDK12; HRs for rPFS and OS numerically favored O + A (rPFS: BRCA2, HR 0.20, 95% CI 0.08–0.44; ATM, HR 0.55, 95% CI 0.20–1.38; CDK12, HR 0.51, 95% CI 0.20–1.18. OS: BRCA2, HR 0.20, 95% CI 0.07–0.48; ATM, HR 0.79, 95% CI 0.33–1.77; CDK12, HR 0.57, 95% CI 0.24–1.27). Conclusions: BRCA2, ATM and CDK12 were the most prevalent single gene mutations and clinical benefit was observed with O + A. Other single gene mutations were rare, limiting interpretation. The greatest treatment benefit was observed in pts with BRCA mutations. Clinical trial information: NCT03732820 . [Table: see text]
Nucleosome profiling at AR binding sites (ARBS) to provide a prognostic tool for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Chao Dai, Lisha Zhu, Heidi Fettke, Shuang Gan, Pan Du, Shidong Jia, Arun Azad
Journal: Journal of Clinical Oncology (2024)

42 Background: Prostate cancer is the second leading cause of cancer death for men in the U.S., and metastatic castration-resistant prostate cancer (mCRPC) is the most advanced form. In previous work, we have reported prognostic significance of PTEN-PI3K-AKT pathway and DNA damage response aberrations detected in cell-free DNA (cfDNA) of mCRPC. Here we utilized nucleosome profiling pattern at androgen receptor (AR) binding sites to further investigate AR signaling pathway dysregulation of mCRPC. Methods: Using the next-generation sequencing PredicineScore liquid biopsy assay (low-pass whole genome sequencing, LP-WGS), we profiled cfDNA fragment coverage centered around AR binding sites (ARBS). For 118 mCRPC patient samples, we quantified sample-level ARBS nucleosome profiling abnormality score (ARBS score) by comparing its centric fragment coverage with normal plasma background using standard Z-score. ARBS score was correlated with clinical outcomes including PSA response rate (PSA RR), progression-free survival and overall survival (OS). Results: By comparing ARBS nucleosome profiling and normal plasma background, we found that mCRPC plasma samples had significant ARBS nucleosome depletion, reflective of transcription factor binding and persistent AR signaling. Notably, ARBS nucleosome depletion was prostate cancer specific, and did not occur in other examined cancer types. ARBS score was highly correlated with tumor fraction (R=0.82), indicating that high tumor fraction mCRPC sample had higher AR binding. Importantly, we found that high ARBS score (&gt;2) in pre-treatment samples (n=86) was associated with significantly shorter OS and lower PSA RR compared with low ARBS (≤2) group for patients receiving AR pathway inhibitor (ARPI) or taxane chemotherapy (13.4 vs. 19.4 months, p=7.3×10 -3 , 45.7% vs. 77.5%, p=5.2×10 -3 ). By integrating genome-wide DNA methylation profiling, we further found that ARBS was hypo-methylated in mCRPC patients, and identified a strong negative correlation between DNA methylation beta value and ARBS score (R=-0.83). Conclusions: ARBS nucleosome profiling abnormality inferred from LP-WGS can serve as a key prognostic tool for mCRPC patients. Patients with high ARBS score had worse clinical outcomes, highlighting the potential clinical utility of cfDNA fragmentomics analysis for mCRPC patient stratification. Integration of mutation, copy number variation and fragmentomics profiling of ARBS may further enhance our understanding of molecular aberrations and treatment outcomes in mCRPC.
Prognostic value of FDG, PSMA, and DOTATATE uptake on PET imaging in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Frederic Pouliot, Fred Saad, Étienne Rousseau, Patrick O. Richard, Atefeh Zamanian, Stephan Probst, Eric Levesque, Vincent Castonguay, Nicolas Marcoux, Daniel Juneau, Michele Lodde, Jean-Baptiste Lattouf, François-Alexandre Buteau, Zineb Hamilou, Michel Pavic, Jean-François Castilloux, Guillaume Bouvet, Amélie Tetu, Brigitte Guérin, Jean-Mathieu Beauregard
Journal: Journal of Clinical Oncology (2024)

31 Background: In mCRPC, fluorodeoxyglucose (FDG) and prostate-specific membrane antigen (PSMA) PET/CT are often used in combination for selecting patients for PSMA-radioligand therapy (PSMA-RLT). Few studies have specifically assessed the prognostic value of FDG+/PSMA- lesions, which exclude patients from PSMA-RLT. Also, little is known about the significance of somatostatin receptor expression, a potential biomarker of neuroendocrine differentiation of mCRPC, which can be assessed with DOTATATE-PET/CT. 3TMPO is a prospective study in progressing mCRPC patients who were imaged with up to 3 PET tracers. Here, we report on patient’s overall survival (OS), with respect to the presence of FDG+/PSMA- and DOTATATE+ lesions. Methods: In 3TMPO (NCT04000776, protocol in PMID 34674367), all patients had 68 Ga-PSMA-617 and 18 F-FDG PET/CT scans. A 68 Ga-DOTATATE scan was ordered if an FDG+/PSMA- lesion was found. For all tracers, positivity was defined as lesion SUVpeak being 1.5x higher than liver SUVmean. Kaplan-Meier with log-rank test was used to assess the difference in OS between groups. Cox regression model was used to quantify the effect of factors predictive of OS. Results: The median [95% CI] OS of the 98 enrolled patients was 10.2 [8.5-11.8] mo. At least one FDG+/PSMA- lesion was found in 45 (45.9%) patients and their OS was shorter than that of the others: 5.6 [4.3-6.9] vs. not reached (p=0.0001). Six (16.2%) of 37 patients who underwent 68 Ga-DOTATATE-PET had ≥1 DOTATATE+ lesion and their OS was shorter than that of patients without a DOTATATE+ lesion: 3.0 [2.2-3.7] vs. 6.4 [1.6-11.1] mo. (p=0.0004). Characteristics significantly associated with worse OS were ECOG, ISUP grade, number of metastases, number of lines of therapy, presence of visceral metastases, FDG and PSMA molecular tumor volumes (MTV) (p&lt;0.05). In a multivariate analysis adjusted for the number of metastases and of treatment lines, the presence of an FDG+/PSMA- lesion increased the risk of death (HR [95% CI]=2.4 [1.4-4.3], p=0.002), and this was also significant after adjusting for both PSMA and FDG-MTV (HR [95% CI]=2.9 [1.4-5.8], p=0.003). Conclusions: mCRPC patients harboring FDG+/PSMA- lesion(s) had a shorter OS than those who did not, and their prognosis was even poorer if they also had DOTATATE+ lesion(s). Upfront FDG/PSMA-PET followed by DOTATATE-PET might help clinicians to guide patient towards palliative care vs. further systemic therapy, including PSMA-RLT. Clinical trial information: NCT04000776 .
Impact of standard-of-truth method on evaluation of a diagnostic PET radiopharmaceutical: Learnings from the phase 3 SPOTLIGHT study.
Authors: Benjamin H. Lowentritt, Albert Chau, Phillip Davis
Journal: Journal of Clinical Oncology (2024)

39 Background: SPOTLIGHT (NCT04186845) evaluated newly approved diagnostic PET radiopharmaceutical 18 F-flotufolastat ( 18 F-rhPSMA-7.3) in patients (pts) with recurrent prostate cancer (PCa). In the absence of the gold standard histopathology, it can be challenging to verify positive findings from a diagnostic agent under investigation, particularly in recurrent PCa where it is neither feasible nor ethical to obtain multiple biopsies from the same patient. Consequently, conventional imaging is often used as a standard of truth (SoT) despite potential for it to be less sensitive than the investigational agent. Here, we explore the impact of SoT methods used in SPOTLIGHT on the study endpoints. Methods: The SPOTLIGHT coprimary endpoints were patient-level verified detection rate (VDR) and combined region-level positive predictive value (crPPV). Patient-level PPV was an exploratory endpoint. Pts with recurrent PCa underwent PET 50–70 min after IV administration of 296 MBq 18 F-flotufolastat. For SoT assessment, the protocol required either histopathology or confirmatory imaging (≤60 and ≤90 days post-PET, respectively). Three blinded readers evaluated the scans, with majority read representing agreement between ≥2 readers. A separate Truth Panel established SoT for all pts. Post-study analysis revealed that, likely due to the study occurring during COVID, some pts had neither histopathology nor post-scan confirmatory imaging. These pts had only baseline/historic imaging as SoT. The present analysis stratified endpoint data according to the SoT method the panel used to verify PET-positive lesions. Results: Of 366 evaluable pts, 69 had histopathology and 297 had only confirmatory imaging for SoT. Of those with an imaging SoT, 90 (30%) had baseline/historic imaging only. As the Table shows, for each endpoint the highest value was obtained when using histopathology as SoT. VDR was ~4-fold higher with histopathology vs baseline/historic imaging, crPPV was 2-fold higher and PPV 2.5-fold. Conclusions: These data illustrate the substantial impact SoT methods can have on clinical trial endpoints and highlight a limitation of evaluating SPOTLIGHT endpoints in a cohort with various SoT methods (Table, column 1). 1 Notably lower endpoint values are achieved when including pts with baseline/historic imaging SoT vs gold standard histopathology. 1. J Urol. 2023; 210:299-311. Clinical trial information: NCT04186845 . [Table: see text]
Real-world economic burden of patients with metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Deborah Kaye, Ibrahim Khilfeh, Erik Muser, Laura Morrison, Ana Urosevic, Frederic Kinkead, Patrick Lefebvre, Dominic Pilon, Daniel J. George
Journal: Journal of Clinical Oncology (2024)

64 Background: In patients with prostate cancer (PC), progression to a metastatic disease stage is associated with substantial decline in prognosis as well as incremental economic burden. There is limited real-world evidence combining clinical data and payer claims to evaluate economic outcomes of patients with mCSPC. This study described healthcare costs of patients with mCSPC before and after the initiation of advanced therapy. Methods: Linked data from the Flatiron Metastatic PC Core Registry and all-payer claims data from Komodo Health Solutions were evaluated (Jan 2016 to Dec 2021). Patients in Flatiron who initiated advanced therapy for mCSPC (index date) in 2017 or later and had a corresponding pharmacy or medical claim in Komodo, following evidence of metastasis in the absence of castration resistance were included. Advanced therapies considered were androgen-receptor signaling inhibitors, chemotherapies, estrogens, immunotherapies, poly ADP-ribose polymerase inhibitors, and radiopharmaceuticals. Patients were excluded if they initiated a clinical trial drug as their index regimen or had &lt;12 months of health insurance eligibility pre-index. All-cause and PC-related total costs (medical and pharmacy) per-patient-per-month (PPPM) were described from a payer’s perspective in the 12-month pre- and post-index period using 2022 US dollars. The post-index period was censored at evidence of castration resistance. Flatiron Health, Inc. did not participate in data analyses. Results: In total, 418 patients with mCSPC were identified (mean age 68 years, 56% white, 53% commercially insured, and 37% on Medicare). Pre-index androgen deprivation therapy was observed in 74% of patients. Pre-index, mean all-cause costs were $2,334 PPPM and PC-related costs were $964 PPPM with $90 PPPM attributable to PC-related pharmacy costs (Table). Post-index, patients averaged 14.5 months of follow-up, in which mean all-cause costs were $8,829 PPPM with PC-related costs of $7,232 PPPM, an increase of &gt;7 times compared to pre-mCSPC therapy initiation. Conclusions: This real-world study demonstrated that costs associated with disease progression in PC are significant and lead to a need for more innovative therapies and medical management in this patient population. Approaches that effectively slow disease progression at earlier stages of PC disease may result in better overall outcomes and lower overall costs associated with progression to metastatic disease. [Table: see text]
Racial disparities in GU cancer metastasis: A comprehensive analysis from 2010-2018.
Authors: Abdul Rahman Al Armashi, Jorge A. Garcia, Jason R Brown
Journal: Journal of Clinical Oncology (2024)

30 Background: Patterns of metastatic spread vary between bladder, kidney, and prostate metastasis. Of these cancers, kidney cancer often spreads to the brain, while prostate cancer is most likely to spread to bone, for example. Sites of metastasis can influence prognosis and in some instances may even direct therapy. The knowledge gap on racial disparities in metastatic patterns merits further investigation. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified bladder, kidney, and prostate cancer patients (2010-2018) in White (W) and Black (B) races. Data on metastasis to the lungs, liver, bones, and brain at diagnosis were extracted. The relative risk (RR) was calculated to compare the metastatic patterns between Black and White patients. P-value, and confidence interval were computed using SPSS 28.0. Results: 3.95% of Black and 1.65% of White patients had metastasis at diagnosis. Black patients had metastasis prevalence of 3.2% lung, 1.8% liver, 4.4% bone, and 0.3% brain. Comparatively, White patients had 1.3%, 0.8%, 3.2%, and 0.3% respectively. For bladder cancer, Black patients had a 60% higher risk for bone and lung metastasis and double the risk for liver metastasis compared to White patients. In kidney cancer, Black patients had a 90% higher brain metastasis risk but 20% lower for bone and lung than White patients. For prostate, Black patients had comparatively heightened risks of bone, lung, and liver metastases by 10%, 20%, and 30%, respectively. Conclusions: Racial disparities are evident in GU cancer metastatic patterns at time of diagnosis. Black patients especially have higher liver metastasis, often associated with poor prognosis. Further studies are vital to unravel biological, socioeconomic, and other contributing factors. [Table: see text]
Survival and fracture risk with radium-223 therapy in metastatic castrate-resistant prostate cancer (mCRPC): A real-world analysis.
Authors: Hanbo Zhang, Jeffrey Graham, Piotr Czaykowski, Joel Roger Gingerich, Bohdan Bybel, David E Dawe
Journal: Journal of Clinical Oncology (2024)

50 Background: Radium-223 is a life-prolonging radionuclide therapy for men with bone-predominant metastatic castrate-resistant prostate cancer (mCRPC). It accumulates at sites of high bone turnover with emerging evidence suggesting use of radium-223 increases risk of pathologic fractures. Bone-protective agents (BPAs) reduce skeletal-related events including pathologic fractures in men with mCRPC. We evaluated real-world outcomes of patients treated with radium-223, including the effect of BPA use on pathologic fracture risk. Methods: This was a single institution retrospective cohort study that included patients with mCRPC treated with radium-223 in Manitoba, Canada from 2014 to 2021. Outcomes of interest included incidence of pathologic fracture, pain response, alkaline phosphatase (ALP) response, and overall survival. Kaplan-Meier method was used for time to event outcomes and multivariable Cox regression models were used to adjust for covariates. Results: We identified 92 patients who received radium-223 for mCRPC (Table). Thirty patients (33%) completed 6 cycles of radium-223. Documented pain relief occurred in 39% of patients. For those with elevated ALP at baseline (n = 46), 57% had at least 30% reduction in total ALP. PSA reduction occurred in 29% with 11% having at least 30% reduction in PSA. Median overall survival (OS) was 9.4 months (95% CI 5.8 to 15.9). Of those who did not receive concurrent BPA, 26% developed a pathologic fracture, compared to 3% who received concurrent BPA during a median follow up of 8.1 months. BPA use was associated with significant delay in time to pathologic fracture (median not reached vs. 15.9 months; HR = 0.20, 95% CI: 0.05 – 0.76, p &lt; 0.05) after adjusting for number of bone metastases and corticosteroid use. Conclusions: In this real-world study, concurrent BPA use was associated with significant reduction in risk of pathologic fractures in mCRPC patients receiving radium-223. BPA administration should be considered for patients receiving radium-223. [Table: see text]
Detection and delineation of intraprostatic lesions (IPLs) using multiparametric magnetic resonance imaging (mpMRI) and prostate specific membrane antigen positron emission tomography (PSMA PET) for patients with prostate cancer: A systematic review and meta-analysis.
Authors: Aneesh Dhar, Lucas Mendez, Jose de Jesus Cendejas-Gomez, Gabriel Boldt, Eric McArthur, Constantinos Zamboglou, Glenn Bauman
Journal: Journal of Clinical Oncology (2024)

287 Background: External beam radiation therapy (EBRT) is a common treatment used for patients with prostate cancer, however, isolated local failures (ILFs) can occur in up to 13% of patients receiving EBRT. Most ILFs occur at the location of the previously known intraprostatic lesions (IPLs). The FLAME trial has shown improved cancer outcomes for patients treated with EBRT who receive a focal radiation boost to their IPL. Both mpMRI and PSMA PET can be used to localize IPL for these patients. Methods: A systematic review and meta-analysis was conducted for the use of mpMRI and PSMA PET for the detection and delineation of IPLs for patients with localized prostate cancer. Trials were included if patients received either mpMRI, PSMA PET, or both, prior to radical prostatectomy (RP). IPLs on RP specimens were used as the reference standard. The quality of the co-registration between imaging and histopathology was assessed as high or low for each study included in the systematic review. Outcomes that were recorded include sensitivity and specificity, among others. A meta-analysis was conducted using a bivariate model to determine the sensitivity, specificity, and area under the receiver operating curve (AUROC) of mpMRI, PSMA PET, and their combination. This systematic review was registered through PROSPERO (CRD42023389092). Results: After exclusions, 20 studies were incorporated into the bivariate meta-analysis. In total, there were 13 studies using mpMRI (n = 541 patients), 12 studies that used PSMA PET (n = 327), and 5 studies that used a combination (n = 180). The pooled sensitivity (95% CI), specificity (95% CI) and AUROC for mpMRI were 64.7% (50.2% – 76.9%), 86.4% (79.7% - 91.1%), and 0.852; the pooled outcomes for PSMA PET were 75.7% (64.0% - 84.5%), 87.1% (80.2% - 91.9%), and 0.889; for their combination, the pooled outcomes were 70.3% (64.1% - 75.9%), 81.9% (71.9% - 88.8%), and 0.796. When reviewing studies with a high-quality co-registration between imaging and histopathology, IPL delineation recommendations included using a 1-2 mm margin when delineating on mpMRI, using a SUV max threshold of 20-30% for PSMA PET, and using the union of mpMRI and PSMA PET when using both modalities. Conclusions: In this study, we conducted a meta-analysis of studies that used mpMRI, PSMA PET or their combination prior to RP for patients with localized prostate cancer. The pooled sensitivity and specificity for each modality had overlapping 95% confidence intervals, suggesting the modalities have similar accuracy in detecting IPLs on RP specimens. There were different delineation recommendations based on the imaging modalities used in studies with a high-quality co-registration of imaging and histopathology.