tbuckley/cabot-search huggingface dataset:
<i>BRCA1/2</i> reversion mutations (<i>BRCA</i>rev) in advanced prostate cancer in the absence of prior PARP inhibitor (PARPi) therapy.
Authors: Douglas I. Lin, Elizabeth L, Natalie Danziger, Huihui Ye, Brennan J. Decker, Ryon P Graf, Jeffrey S. Ross, Julia A. Elvin, Rana R. McKay
Journal: Journal of Clinical Oncology (2024)

5056 Background: In prostate cancer (PCA), BRCA1/2 alterations confer sensitivity to PARPi; however, in cases other than PCA with homozygous BRCA deletions, somatic BRCArev may restore BRCAfunction and mediate treatment resistance. In this study, we analyzed liquid biopsies of men with advanced PCA to (1) identify BRCArev, (2) to determine the clinical context in which BRCArev developed, and (3) to ascertain potential effect of prior chemotherapy on duration of PARPi response. Methods: BRCA1/2mutations were examined via liquid biopsies (FoundationOne Liquid CDx) during the course of clinical care for PCA patients during a 12-month period (from 01/2023 to 12/2023). Clinicopathological features and treatment history were extracted from medical records and/or treating oncologists’ notes. Results: Among 416 PCA patients with detected BRCA1/2 alterations, 25 (6.0%) patients harbored BRCArev that were predicted to restore BRCA function. Ten of 25 (40%) patients had detailed clinical and treatment history available. In three of 10 (30%) patients, somatic BRCArev were detected in the absence of prior PARPi therapy. All three PARP-naïve patients had been previously treated with chemotherapy (platinum or docetaxel) and radiation. Two patients had castration-resistant prostatic adenocarcinoma, while the third patient had de novo high-stage prostatic small cell neuroendocrine carcinoma without prior androgen deprivation. In all three PARP-naïve patients, multiple reversion mutations were detected per patient post-chemotherapy/radiation. Two of the three patients were predicted to have an original germline BRCA2alteration. The remaining 7 BRCArev-positive patients (70%) had prior PARPi treatment (all Olaparib). In PARPi-treated patients, duration of PARPi treatment prior to identification of BRCArev ranged from 5 to 24 months. 4 out of 7 PARPi-treated patients had received prior docetaxel, and duration of PARPi response was longer in chemo-naïve patients compared with those who had received prior docetaxel before PARPi (Mean: 18.6 vs 8.3 months, respectively). Conclusions: In men with BRCA-mutated PCA, chemotherapy and/or radiation may induce BRCArev in the absence of PARPi therapy. Testing of post-chemotherapy or radiation patients for BRCArev may be warranted prior to the start of PARPi therapy in patients with PCA. Our results support early PARPi therapy prior to radiation or chemotherapy as post-chemotherapy/radiation BRCArev may potentially dampen the future success of subsequent PARPi strategies.[Table: see text]
Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with <sup>177</sup>Lu-PSMA-617 versus change of ARPI in PSMAfore.
Authors: Johann S. De Bono, Michael J. Morris, Oliver Sartor, Xiao X. Wei, Karim Fizazi, Ken Herrmann, Josep M. Piulats, Hakim Mahammedi, Christopher Logothetis, Daniel J. George, Lamis K. Eldjerou, Connie Wong, Louise Barys, Nisha Rajagopal, Theodoulos Rodosthenous, Kim N. Chi
Journal: Journal of Clinical Oncology (2024)

5008 Background: [ 177 Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). In this exploratory analysis, associations between baseline circulating tumor DNA (ctDNA) and outcomes were assessed. Methods: Patients were randomized 1:1 to 177 Lu-PSMA-617 (7.4 GBq Q6W; 6 cycles) or ARPI change (abiraterone/enzalutamide). Patients known to have actionable mutations (e.g. BRCA) were excluded. The primary endpoint was rPFS. Baseline plasma ctDNA was analyzed using a customized 585-gene sequencing assay. ctDNA fraction was assessed in all samples passing quality control. Alterations in key prostate cancer drivers (prevalent in &gt;10% participants) were assessed in samples with ctDNA fraction &gt;1%. Univariate Cox regression (reference: ARPI change) was used to assess association of ctDNA fraction or alterations with rPFS, prostate-specific antigen response (≥50% decline; PSA50) and RECIST response (RR) at the June 21, 2023 data cutoff. Results: Of 360 samples from 468 patients, 255 passed quality control and 156 had ctDNA fraction &gt;1% (median 5.85%; range 0–85). Detection of ctDNA alterations was comparable between arms and with published data. Median rPFS was shorter for patients with ctDNA fraction &gt; versus ≤1% (HR 2.753; 95% CI 1.957–3.872; p&lt;0.0001) (Table); ctDNA fraction &gt;1% was also associated with worse RR and PSA50 response. Median rPFS was shorter for patients with detected versus undetected AR(HR 1.954; 95% CI 1.333–2.865; p&lt;0.001), TP53(1.655; 1.13–2.426; p&lt;0.01) and PTEN(1.62; 1.018–2.578; p&lt;0.05) alterations. Median rPFS was longer with 177 Lu-PSMA-617 versus ARPI change in patients with detected AR, TP53, PTEN(Table) , PI3K pathway and DNA repair pathway alterations. There was no significant association between ctDNA alterations and PSA50 or RR. Conclusions: ctDNA fraction &gt;1% and AR, TP53and PTENalterations were associated with worse outcomes in PSMAfore regardless of treatment. Nonetheless, patients with these negative prognostic biomarkers did better with 177 Lu-PSMA-617 than with ARPI change. Clinical trial information: NCT04689828 . [Table: see text]
Comparing overall survival in patients with metastatic prostate cancer using PSA levels: A multivariate analysis using a national database.
Authors: Anas Albawaliz, Rohit Kumar, Pranali Santhoshini Pachika
Journal: Journal of Clinical Oncology (2024)

e17089 Background: Prostate - specific antigen (PSA) is a useful biomarker for detection of prostate cancer and for risk classification in addition to TNM classification and Gleason score. Data is limited in determining its role in prognostication. The purpose of our study is to learn the impact of PSA value at the time of diagnosis on overall survival in patients with de novo metastatic prostate cancer. Methods: The National Cancer Database (NCDB) 2016-17 was queried to identify all patients diagnosed with de novo metastatic prostate adenocarcinoma. The demographic and clinical characteristics were compared using Pearson’s chi-square test between patients with PSA&lt;98 ng/mL versus &gt;=98 ng/mL. A multivariate cox regression analysis was done to determine the survival difference between the two groups. Results: The NCDB database found a cohort of 18,157 patients with de novo metastatic prostate cancer. A total of 8593 patients had PSA values below 98, while 9564 patients had PSA levels equal to or above 98. Multivariate cox regression analysis was done, and results indicated HR of 1.11 with 95% CI 1.07-1.13 and p value &lt;0.001, indicating 11% worse survival in patients with higher PSA. Patients were further stratified based on age, race, and sites of metastasis. The results were consistent across all groups, with a significant p-value of &lt;0.001. Conclusions: Our study indicates that a higher PSA value at the time of diagnosis is associated with a lower overall survival in patients with de novo metastatic prostate cancer. Further prospective studies with potentially higher PSA thresholds are needed to validate this correlation. Should concordant results be obtained, this may suggest utilizing more aggressive treatment strategies in this subset of patients to improve clinical outcomes. [Table: see text]
Impact of surgical margins on mortality after robotic radical prostatectomy.
Authors: Tom Edward Ahlering, Zaki Zeidan, Joshua Tran, Yeagyeong Hwang, Linda My Huynh, Mai Xuan Nguyen, Whitney Zhang
Journal: Journal of Clinical Oncology (2024)

e17101 Background: Positive surgical margins (PSMs) following radical prostatectomy (RP) have long been seen as inherently unfavorable. Despite this belief, there has not been as much evidence supporting unifocal PSMs (UPSM) and prostate cancer-specific mortality (PCSM). Some have reported that multifocal PSM (MPSM) seems to be associated with PCSM. In this study, we examine and compare the impact on PCSM between percent tumor volume (PTV) and MPSMs. Methods: Prospectively collected data for 1552 patients with complete data who underwent RARP by a single surgeon between 2002 and 2018. The primary outcome was comparing risk of PCSM versus increasing pTV. Patients were categorized into pTV groups at a cutoff 40%. PSMs were categorized as negative (NSM), unifocal (UPSM), or multifocal (MPSM). Kaplan-Meier (KM) was used to assess time to OM and PCSM. Results: Men with 40-100% PTV were significantly older and had more advanced grades and stages. High PTV demonstrated a significantly greater risk of PSMs (both unifocal and multifocal), BCR, PCSM, and OM at 15 years. Before including PTV in the multivariate analysis, MPSM independently predicted PCSM, but UPSM did not. However, MPSMs lost their predictive significance when PTV was included. High-stage and Gleason grade group were independent predictors in both analyses. High PTV demonstrated shorter time to PCSM. Conclusions: Our study further challenges the common belief that PSMs are inherently oncologically adverse. Instead, MPSMs appear to signify more voluminous but more importantly aggressive underlying disease, which is the contributing factor for the adverse oncologic outcomes. We emphasize monitoring PTV as a key predictor of long-term adverse oncologic effects as a more reliable predictor of PCSM. Minimizing PSMs remains a critical surgical principle, but in prostate cancer, it needs to be weighed against urinary and sexual function outcomes.
Utility of ctDNA burden as a prognostic biomarker for efficacy in TALAPRO-2: A phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Arun Azad, Karim Fizazi, Douglas Laird, Nobuaki Matsubara, Ugo De Giorgi, Consuelo ButtIgliero, Lawrence Ivan Karsh, Jae Young Joung, Steven Yip, Stefanie Zschaebitz, Lee A. Albacker, Cynthia G. Healy, Xun Lin, Jijumon Chelliserry, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2024)

5020 Background: TALAPRO-2 (NCT03395197) demonstrated that 1L TALA + ENZA significantly improved radiographic progression-free survival (rPFS) vs PBO + ENZA for pts with mCRPC. ctDNA burden is a candidate prognostic biomarker with potentially broad utility across treatments and tumor types. We assessed the potential prognostic utility of baseline (BL) ctDNA burden and changes in ctDNA burden at Week 9 (WK 9) in TALAPRO-2 pts. Methods: Retrospectively analyzed serial ctDNA samples from BL and WK 9 were assessed using FoundationOneLiquid CDx. Plasma tumor fraction was calculated based on aneuploidy (Husain et al. JCO Precis Oncol. 2022. PMID: 36265119). We categorized ctDNA burden as high (ctDNA burden quantifiable) vs low (unknown ctDNA burden). Data cutoff date was August 16, 2022. Results: In the all-comers intent-to-treat population, 678 pts were evaluable for ctDNA burden at BL: 26% (89/337) of TALA + ENZA pts were ctDNA-high and 74% (248/337) were ctDNA-low; 29% (98/341) of PBO + ENZA pts were ctDNA-high and 71% (243/341) were ctDNA-low. High ctDNA burden at BL was prognostic of inferior rPFS in the TALA + ENZA and PBO + ENZA arms (Table). A relatively favorable median rPFS was observed for pts with low ctDNA at BL and WK 9 for TALA + ENZA (n=206) and PBO + ENZA (n=207), as reported in the Table. At WK 9, 72 pts in the TALA + ENZA and 77 pts in the PBO + ENZA arms were evaluable for ctDNA conversion from high to low. In both treatment arms, conversion from high to low ctDNA was prognostic of improved rPFS vs pts who remained ctDNA-high (Table). Pts who remained ctDNA-low had a more favorable rPFS vs conversion from high to low ctDNA: TALA + ENZA, hazard ratio (HR) 95% confidence interval (CI), 0.45 (0.29–0.71), P=0.0003; PBO + ENZA, 0.34 (0.23–0.52), P&lt;0.0001). Conclusions: High ctDNA burden at BL was negatively prognostic, and ctDNA conversion from high to low at WK 9 was prognostic of improved rPFS in TALAPRO-2. Limitations included not all clinical trial sites were able to perform ctDNA collection and most samples were below the limit of quantification. These results support the broad prognostic utility of ctDNA burden in mCRPC. Clinical trial information: NCT03395197 . [Table: see text]
CYP11A1 inhibitor MK-5684 versus next-generation hormonal agent (NHA) switch in patients with metastatic castration-resistant prostate cancer (mCRPC) after NHA and taxane-based chemotherapy: Phase 3 MK-5684-003 trial.
Authors: Evan Y. Yu, Yue Song, Christian Heinrich Poehlein, Charles Schloss, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2024)

TPS5113 Background: Androgen receptor (AR) signaling remains a key driver of prostate cancer even after progression on androgen-directed therapies. Activating AR ligand binding domain (AR-LBD) somatic point mutations are a common mechanism of resistance to androgen-directed therapies in patients with mCRPC. MK-5684 (ODM-208) is an oral, nonsteroidal inhibitor of cytochrome P450 11A1 (CYP11A1), which catalyzes the first and rate-limiting step of steroid biosynthesis. Inhibition of CYP11A1 by MK-5684 suppresses the production of all steroid hormones and their precursors that may promiscuously activate the AR signaling pathway. In the phase 1/2 CYPIDES trial, MK-5684 showed antitumor activity in patients with heavily pretreated mCRPC, especially in those with AR-LBD mutations. The randomized, open-label, phase 3 MK-5684-003 trial (NCT06136624) is evaluating the efficacy and safety of MK-5684 versus NHA switch in patients with mCRPC previously treated with NHA and taxane-based chemotherapy. Methods: Eligible patients havemCRPC (unselected for AR-LBD mutations) that progressed on androgen deprivation therapy ≤6 months before screening and during or after treatment with 1 NHA for nonmetastatic (nm) hormone-sensitive prostate cancer (HSPC), nmCRPC, mHSPC, or mCRPC for ≥8 weeks (≥14 weeks with bone progression), and also progressed during or after 1 or 2 taxane-based chemotherapies for mCRPC. Approximately 1200 patients (300 with and 900 without AR-LBD mutations) will be randomly assigned 1:1 to receive MK-5684 5 mg PO BID (+ dexamethasone 1.5 mg and fludrocortisone 0.1 mg QD) or enzalutamide 160 mg PO QD (if prior abiraterone) or abiraterone acetate 1000 mg PO QD (+ prednisone 5 mg BID; if prior enzalutamide/darolutamide/apalutamide). Randomization to treatment will be stratified by measurable disease (yes/no), disease AR-LBD mutation status (positive/negative), and prior cabazitaxel use (yes/no). Treatment will continue until radiographic disease progression (verified per Prostate Cancer Working Group 3 [PCWG3]–modified RECIST v1.1 by blinded independent central review [BICR]), unacceptable toxicity, or other discontinuation criteria are met. Tumor assessments will be performed every 8 weeks up to week 24, then every 12 weeks thereafter. Dual primary end points are radiographic PFS (per PCWG3-modified RECIST v1.1 by BICR) and OS in patients with AR-LBD mutation-positive and -negative disease, separately. Secondary end points include time to initiation of first subsequent anticancer therapy or death; ORR and DOR per PCWG3-modified RECIST v1.1 by BICR; time to pain progression; time to prostate-specific antigen progression; time to first symptomatic skeletal-related event; and safety and tolerability. Enrollment is ongoing. Clinical trial information: NCT06136624 .
A randomized phase II study of ADT + abiraterone versus ADT + abiraterone + docetaxel in patients with low-volume metastatic hormone-sensitive prostate cancer.
Authors: Sarah Elizabeth Fenton, Masha Kocherginsky, David James VanderWeele, Maha H. A. Hussain
Journal: Journal of Clinical Oncology (2024)

TPS5121 Background: The PEACE-1 and ARASENS phase III trials showed benefit of “triplet” therapy in patients with metastatic hormone sensitive prostate cancer (mHSPC). Triplet therapy is defined as androgen deprivation therapy (ADT), docetaxel and an androgen receptor signaling inhibitor. Both trials showed improved outcomes in patients with a high volume of disease per CHAARTED criteria (≥ 4 bone lesions with ≥1 beyond the axial skeleton or visceral metastasis). The benefit was less clear in patients with low volumes of disease, this may be due to the use of docetaxel as the control arm in this patient population. In the CHAARTED study the benefit of docetaxel in addition to ADT was most pronounced in patients with high volume mHSPC, and the benefit was less certain in low volume disease. To address this uncertainty, we are conducting this phase II trial evaluating ADT/abiraterone versus ADT/abiraterone plus docetaxel in patients with low volume mHSPC. Methods: This is a multisite, randomized trial of ADT (physician’s choice) and abiraterone (1000mg daily + 5 mg prednisone) versus ADT, abiraterone and docetaxel (75 mg/m 2 q3 weeks for 6 cycles). Patients may have started ADT up to 12 weeks prior to randomization. Key eligibility criteria include a tissue-confirmed diagnosis of prostate cancer (PCa) and evidence of metastatic disease on CT, MRI and/or bone scan that meets CHAARTED criteria for low volume disease. Recurrent PCa and exposure to ADT prior to the diagnosis of metastatic disease are allowed, as is concurrent treatment with radiation therapy. The primary objective is to assess and compare radiographic progression free survival (rPFS) between treatment arms. Power calculations assume the median rPFS of the control arm is 33 months (based on the LATITUDE trial) versus 55 months in the docetaxel arm (based on the PEACE-1 trial). A sample size of 120 patients will provide 80% power with a one-sided α = 0.10 Type I error rate based on the log rank test to detect a hazard ratio = 0.60. Assuming a 36-month accrual duration and an additional 3 years of follow up, a total of 70 events are expected to occur on this study. The study will enroll 150 patients (75 per arm) to obtain 120 evaluable patients (assuming a 20% attrition rate). Secondary endpoints include overall survival, PSA response rate, overall response rate, time to castration resistant PCa and time to initiation of subsequent anti-neoplastic therapy. Exploratory endpoints include quality of life assessments and rates of adverse events. Enrollment in this trial began in Dec 2023. It is open at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and other satellite sites affiliated with Northwestern University. Clinical trial information: NCT06060587 .
Sequential ADT and abiraterone acetate plus prednisone versus combined ADT with abiraterone acetate plus prednisone for metastatic castration-sensitive prostate cancer: A propensity score-matched study.
Authors: Zhenyu Yang, Diwei Zhao, Jun Wang, Xingbo Long, Dong Chen, Fangjian Zhou, Yonghong Li
Journal: Journal of Clinical Oncology (2024)

e17075 Background: Previous studies showed that combination of androgen deprivation therapy (ADT) with abiraterone acetate plus prednisone was associated with longer survival than ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). The aim of this retrospective propensity score-matched study was to compare the effects of sequential treatment of ADT and abiraterone acetate plus prednisone (sequential treatment cohort), and combination treatment of ADT with abiraterone acetate plus prednisone (combination treatment cohort), in men with newly diagnosed mCSPC. Methods: The sequential treatment cohort received ADT or ADT plus first-generation nonsteroidal antiandrogen (NSAA) as first-line therapy, then ADT and abiraterone acetate plus prednisone after progression. The combination treatment cohort received ADT and abiraterone acetate plus prednisone as first-line therapy. Patients with newly diagnosed mCSPC treated with ADT, ADT plus first-generation NSAA, or ADT plus abiraterone acetate in our center between June 2014 and July 2022, were respectively identified. Patients treated with sequential treatment or combination treatment were evaluated through propensity score matching (PSM) based on baseline clinical characteristics. The primary outcome was abiraterone failure-free survival (aFFS). Secondary outcomes including overall survival (OS), PSA response. Results: Clinical characteristics were balanced after PSM and 117 patients were included in each cohort. The aFFS was 30.7 and 30.6 months in sequential and combination treatment cohort, respectively, no statistically significant difference was observed (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.64 -1.27; p = 0.526). Similarly, there was no statistically significant difference in overall survival (OS, HR 0.92, 95% CI 0.57 -1.49; p = 0.388) between sequential and combination treatment. Conclusions: Patientswith newly diagnosed mCSPC treated with sequential ADT and abiraterone acetate plus prednisone, had similar aFFS and OS, compared to men treated with combined ADT and abiraterone acetate plus prednisone, according to our preliminary results. Our data indicate that sequential treatment of ADT and abiraterone acetate might be considered as an alternative to newly diagnosed mCSPC.
Exploring T Cell Receptor Repertoires in Myocardial Diseases
Authors: DiyaaElDin Ashour, Kenz Le Gouge, Peter P. Rainer, Encarnita Mariotti-Ferrandiz, Gustavo Campos Ramos
Journal: Circulation Research (2024)

Mounting experimental and clinical evidence has revealed that adaptive immune mechanisms targeting myocardial antigens are triggered by different forms of cardiac injury and impact disease progression. B and T lymphocytes recognize specific antigens via unique adaptive immune receptors generated through a somatic rearrangement process that generates a potential repertoire of 10