bluuebunny/crossref_metadata_2025_split huggingface dataset:
Utilization of metastatic hormone sensitive prostate cancer (mHSPC) treatment in a community oncology practice setting.
Authors: Conner Terri , Appukkuttan Sreevalsa , Kong Sheldon , Jhaveri Jay , Ko Gilbert , Kalayeh Bashir , He LiHong , Hauser Robert Sean , Loaiza-Bonilla Arturo 
Published: March 2023

86 Background: Treatment options for mHSPC have continued to evolve. While androgen deprivation therapy (ADT) has been the backbone treatment, more recently early use of docetaxel and/or novel androgen receptor inhibitors (nARIs) has demonstrated improved clinical outcomes. This study assessed real-world treatment among mHSPC patients who received at least one line of therapy (LoT). Methods: A retrospective observational study utilizing de-identified health records from five Cancer Treatment Centers of America (CTCA) included patients with metastatic prostate cancer who were treated with ADT, docetaxel or nARIs at CTCA for 6+ months between 1/2015-3/2021. Treatment patterns were observed from first LoT to metastatic castration resistance, death, or lost-to-follow-up until 3/2022. LoT was defined as first to last date of active drug therapy, not including long-term hormone agonists. First LoT was defined as initial regimen with no new drugs added 30+ days after start date. Patient characteristics, proportion and duration of each LoT, and reasons for early discontinuation were gathered using structured data elements and chart abstraction. Results: The characteristics of the 523 patients in this study were as follows: mean (SD) age 62 (8) years, 60% white and 33% black, 53% with commercial insurance, 75% with ECOG 0-1, and 65% with bone metastasis at diagnosis. Median follow-up time was 2.9 years. The most common LoT 1 regimen was either ADT alone or ADT with first generation androgen receptor inhibitors (FGARI) (table below). 46% received a second and 15% received a third LoT. Mean (SD) duration of first and second active LoTs were 12 (11.8) and 10 (11.1) months, respectively. Among the 65% and 78% patients who discontinued therapy in LoT 1 and 2, respectively, the majority discontinued due to progression of disease (35% LoT 1 and 53% LoT 2) followed by patient choice (23% LoT 1 and 18% LoT 2). Conclusions: Despite recommendations from guidelines on early intensification of therapy in mHSPC, in this contemporary cohort we find that most patients received either ADT alone or ADT ± FGARI in LoT 1 while chemotherapy and nARIs were initiated predominantly in later lines. Most patients discontinued LoT 1 due to disease progression which may suggest undertreatment and need for improved outcomes. Further studies are needed to assess the factors associated with non-intensification of treatments. [Table: see text]
Real-world homologous recombination repair (HRR) mutation testing patterns in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) in the United States (US).
Authors: Barata Pedro C. , Montgomery Rachel , Last Matthew , Gillespie-Akar Liane , Nazari Jonathan , Niyazov Alexander 
Published: March 2023

99 Background: A subset of pts with metastatic prostate cancer have HRR mutations. These can be either germline or somatic mutations. Previous studies have established a prognostic and predictive role of HRR mutations and there are ongoing trials (e.g., TALAPRO-3, AMPLITUDE) exploring combination strategies of poly-ADP ribose polymerase inhibitors (PARPi) with novel hormonal therapies (NHT). Therefore, it is relevant to establish baseline HRR testing rates in the real-world setting. This study assessed real-world (rw) HRR testing patterns in pts with mCSPC in the US and described characteristics of tested vs untested pts. Methods: Data were drawn from the Adelphi Prostate Cancer Disease Specific Programme; a point-in-time questionnaire administered to oncologists and urologists in the US between January-August 2020. Physicians abstracted medical records for the next 4-9 pts receiving active drug treatment for mCSPC. Study variables included pt demographics, clinical factors, physician characteristics, and testing status for at least 1 of 12 HRR genes of interest ( ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C). Pt demographics and clinical characteristics were compared between groups using t-tests for continuous and chi-squared or Fisher’s exact test for categorical variables. A multiple logistic regression model was used to assess factors associated with odds of HRR testing. Results: A total of 71 physicians reported on 204 pts with mCSPC. The median age was 68.8. 57/204 (28%) pts were tested for HRR mutations using germline or tumor testing. Pts who were not HRR tested were older compared to HRR tested pts (69.6 vs 66.8, P = 0.038). More pts currently receiving care by an oncologist had a HRR mutation test vs. pts currently receiving care by a urologist [50/156 (32%) vs 7/48 (15%), P =0.02]. According to the multiple logistic regression model, having a known family history of prostate cancer [OR = 3.9 (95% CI: 1.1 – 13.6); P = 0.04], and having visceral metastases at mCSPC diagnosis [OR=4.9 (95% CI: 2.0 – 12.1); P = 0.001] were associated with a significantly higher odds of receiving a HRR mutation test. Conclusions: In this rw US study of adult patients with mCSPC, most patients did not receive HRR testing. Disparities in HRR mutation testing were observed, suggesting that clinical characteristics may influence decisions to test for HRR mutations. Focused efforts to increase HRR mutation testing should be implemented.
Circulating tumor DNA analysis of IMbassador250: Association of ctDNA fraction, AR alterations and therapy outcome in mCRPC.
Authors: Sweeney Christopher , Graf Ryon , Fabrizio David , Yuen Kobe , Wongchenko Matthew J. , Gupta Pratyush , Hegde Priti , Oxnard Geoffrey R. , Powles Thomas 
Published: March 2023

LBA249 Background: IMbassador250 was a prospective phase III international trial which showed no overall survival (OS) benefit for adding atezolizumab to enzalutamide for men with mCRPC who had prior progression on abiraterone. We hypothesized that genomic biomarkers in ctDNA may identify patients who have poorer OS with 2nd generation novel hormonal therapy. Methods: Pre-treatment (but post-abiraterone progression) plasma samples from IMbassador250 were submitted for comprehensive genomic profiling using FoundationOne Liquid CDx. We detected elevated ctDNA tumor fraction (TF) using a novel algorithm that incorporates aneuploidy as well as tumor-derived short variant signal. A pre-specified TF cutoff of ≥ 2% was defined as high. A prospective-retrospective biomarker statistical analysis plan was developed in accordance with Simon Criteria, pre-specifying analyses, cutoffs, and power assessments. Results: 494 baseline plasma specimens were evaluable. The TF high group [371 (74%)] had significantly shorter OS than TF low (median 11.0 vs. 22.1 months, HR 4.3, 95% CI 3.0 – 6.1, p < 0.0001) (primary endpoint). Pre-specified supportive analyses compared the performance to prognosticate OS (concordance [std error]) of baseline PSA alone (0.65 [0.63 – 0.67]) to a model consisting of all evaluable baseline features including PSA, treatment arm, age, race, ECOG score, hemoglobin, alkaline phosphatase, albumin, number of metastatic sites, and sites of metastasis (0.71 [0.70 – 0.73]) to TF alone (0.72 [0.71 – 0.73]) to all features plus TF (0.76 [0.74 – 0.77]). Likelihood ratio test for improvement of OS prediction by adding TF to all available clinical features: p < 0.0001. Focusing on the patients with TF ≥ 2% (n = 371) exploratory analysis observed less favorable outcomes with detection of AR amplifications (n = 203 [55%], HR: 1.4, 95%CI: 1.1 – 1.8), while individual AR mutations were not as strongly associated with OS: L702 ([16%], HR: 1.2, 95%CI: 0.88 – 1.7), W742 ([4.3%], HR: 0.59, 95%CI: 0.30 – 1.2), H875 ([9.4%], HR: 0.71, 95%CI: 0.46 – 1.1), T878 ([25.3%], HR: 0.86, 95%CI: 0.65 – 1.1). Conclusions: In this cohort TF < 2% at baseline is strongly associated with favorable OS on enzalutamide after progression on abiraterone compared to TF ≥ 2%. TF alone has comparable discriminatory ability to anticipate overall survival compared to all available clinical features combined, and adds significant prognostic power when combined with clinical features in this setting. AR amplifications, but not mutations, further improve strengths of association. Clinical trial information: NCT03016312 .
VIOLET: A phase I/II trial evaluation of radioligand treatment in men with metastatic castration-resistant prostate cancer with [161Tb]Tb-PSMA-I&T.
Authors: Buteau James Patrick , Kostos Louise Kathleen , Alipour Ramin , Jackson Price , McIntosh Lachlan , Emmerson Brittany , Haskali Mohammad B , Yeung Theresa , Xie Sophia , Medhurst Elizabeth , Ravi Rajeev , Gonzalez Brian D. , Fettke Heidi , Ng Nicole , Docanto Maria , Bukczynska Patricia , Blyth Benjamin , Furic Luc , Azad Arun , Hofman Michael S 
Published: March 2023

TPS281 Background: [177Lu]Lu-PSMA is an effective class of therapy for men with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response is partially explained by the presence of micrometastatic deposits. Single tumor cells and micrometastases are energy-sheltered deposits receiving low absorbed radiation, due to the ~0.7mm mean path-length of Lutetium-177 (177Lu). Terbium-161 (161Tb) has abundant emission of Auger electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. 161Tb has shown superior in-vitro and in-vivo results in comparison with 177Lu. We hypothesize that [161Tb]Tb-PSMA-I&T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 to 36 men with progressive mCRPC. The phase I dose-escalation is designed with a 3+3 model to establish the safest dose of [161Tb]Tb-PSMA-I&T (dose levels: 4.4, 5.5 and 7.4 GBq). The maximum tolerated dose (MTD) will be defined as the highest dose level at which a dose-limiting toxicity occurs in less than 1/3 or 2/6 participants. The phase II dose-expansion will include 24 participants at the MTD. Up to six cycles of [161Tb]Tb-PSMA-I&T will be administered intravenously every six weeks, with each subsequent dose for each patient reduced by 0.4GBq. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy and a second-generation anti-androgen, PSMA-positive disease on PSMA PET/CT (SUVmax ≥20), no sites of discordance on FDG PET/CT, adequate bone marrow, hepatic and renal function, ECOG performance status ≤2, and no prior treatment with another radioisotope. The co-primary objectives are to establish the MTD of [161Tb]Tb-PSMA-I&T, and safety profile [CTCAE v5.0]. Secondary objectives include measuring absorbed radiation dose [Gray], evaluating anti-tumour activity [PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective response rate], and evaluation of pain [BPI-SF] and health-related quality of life [FACT-P and FACT-RNT] over the first 12 months after treatment commences. Exploratory objectives include ctDNA analysis at baseline, during treatment and at progression, and optional tissue biopsies, to determine biomarkers of treatment response and resistance. Patient enrolment began in October 2022, with recruitment expected to continue for 24 months. Clinical trial information: NCT05521412 .
CAPItello-280: A phase III study of capivasertib and docetaxel versus placebo and docetaxel in metastatic castration-resistant prostate cancer.
Authors: Crabb Simon J. , Ye Ding-Wei , Uemura Hirotsugu , Morris Thomas , Gresty Christopher , Logan Jill , Rooney Claire , Foxley Andrew , Carducci Michael Anthony 
Published: March 2023

TPS287 Background: Docetaxel is the standard first-line chemotherapy for patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed on an androgen receptor-targeted agent (ARTA; typically, abiraterone, enzalutamide, apalutamide, or darolutamide). However, most patients develop chemotherapy resistance, and median overall survival (OS) remains under 3 years. Preclinical studies have associated phosphoinositide 3-kinase (PI3K)/protein kinase (AKT)/phosphatase and tensin homolog (PTEN) pathway signaling with the development of mCRPC and with resistance to taxane chemotherapy. The ProCAID Phase II trial (NCT02121639) examined whether adding capivasertib, a potent, selective inhibitor of all three AKT isoforms (AKT1/2/3), to docetaxel chemotherapy improved clinical outcomes. Although no difference in the primary endpoint (composite progression-free survival [PFS]) was detected, OS, a secondary endpoint, was extended in the capivasertib plus docetaxel treatment group. A subsequent follow-up analysis at advanced maturity suggested that the OS benefit in ProCAID was restricted to patients who had received prior treatment with an ARTA. Methods: CAPItello-280 is a Phase III study to confirm the efficacy and safety of capivasertib in combination with docetaxel compared with placebo and docetaxel in patients with mCRPC who have not previously received chemotherapy for mCRPC, but whose disease has progressed despite treatment with an ARTA in any setting. Approximately 790 patients will be randomized 1:1 to receive either capivasertib or matching placebo (320 mg orally, twice daily [BD], 4 days on, 3 days off) plus docetaxel (75 mg/m2 on day 1 of each 21-day cycle for 6–10 cycles, with prednisone or prednisolone 5 mg BD or 10 mg once daily) with a background of continued androgen deprivation therapy until disease progression, unacceptable toxicity, death, or withdrawal of consent. The primary endpoint is OS; secondary endpoints include radiographic PFS, time to pain progression, symptomatic skeletal events, safety, and tolerability. Recruitment began in March 2022 and is planned at 207 study sites in 20 countries, including the USA, Canada, Europe, South America, and Asia-Pacific. Clinical trial information: NCT05348577 .
A phase 2 expansion study of ARV-766, a PROTACandrogen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Petrylak Daniel P. , Stewart Tyler F. , Gao Xin , Berghorn Elmer , Lu Haolan , Chan Edward , Gedrich Richard , Lang Joshua Michael , McKean Meredith 
Published: March 2023

TPS290 Background: Patients with mCRPC inevitably develop resistance to available therapies and lack curative options. In patients treated with novel hormonal agents (NHAs), mutations can develop in the ligand-binding domain (LBD) of the AR gene, some of which are associated with resistance to current therapies and disease progression. ARV-766 is a novel, potent, orally bioavailable proteolysis targeting chimera (PROTAC) protein degrader that degrades not only wild-type AR but also clinically relevant AR LBD mutants, including the most prevalent AR L702H, H875Y, and T878A mutations. Here we describe a phase 2 expansion study to evaluate the clinical activity and safety of ARV-766 in men with mCRPC who have experienced disease progression on prior NHA therapy. Methods: This phase 2 cohort expansion is part of an open-label, first-in-human, phase 1/2 clinical trial of ARV-766 in men (aged ≥18 years) with histologically, pathologically, or cytologically confirmed mCRPC and Eastern Cooperative Oncology Group performance status score of 0 or 1. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analog or inhibitor or orchiectomy is required. Patients enrolled in the cohort expansion must have received 1–3 prior NHAs (eg, abiraterone or enzalutamide) and ≤2 prior chemotherapy regimens. Following completion of dose escalation in the phase 1 portion of the study, which is evaluating the safety and tolerability of ARV-766, 2 doses (100 mg and 300 mg administered orally once daily in 28-day cycles) were selected for the phase 2 cohort expansion. The primary objectives of the cohort expansion study are to evaluate the antitumor activity of ARV-766 based on the overall response rate (per Response Evaluation Criteria in Solid Tumors) and the rates of prostate-specific antigen (PSA) declines of 30% (PSA30) and 50% (PSA50). Enrollment in the phase 2 expansion study is ongoing. Clinical trial information: NCT05067140 .
A phase II single-arm trial of niraparib in platinum-sensitive metastatic castration-resistant prostate cancer with DNA repair defects (PLATPARP).
Authors: Narayan Vivek , Torres Alexandra , Seger Philip , Aaron Megan , Louie Jennifer , Lee Daniel , Haas Naomi B. , Takvorian Samuel U , Maxwell Kara Noelle , Domchek Susan M. 
Published: March 2023

TPS291 Background: Platinum-based chemotherapy, either as monotherapy or in combination with taxanes, is increasingly used for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring germline and/or somatic homologous recombination repair gene mutations (HRRm). However, clinical responses with platinum-based therapy are often of limited duration and limited by cumulative toxicities. The PARP inhibitor (PARPi) olaparib is approved for the treatment of mCRPC patients with pathogenic HRRm after progression on enzalutamide or abiraterone. Importantly, sensitivity to platinum-based chemotherapy may predict improved clinical outcomes with PARPi, and ‘maintenance’ PARPi strategies are routinely used in patients with advanced ovarian and pancreatic malignancies with HRRm with initial clinical response to platinum chemotherapy. We hypothesize that maintenance niraparib, a PARPi with demonstrated activity in mCRPC with HRRm, will prolong clinical responses to platinum-based chemotherapy with acceptable toxicity in mCRPC patients harboring germline and/or somatic HRRm. Methods: We are conducting an open-label, single-arm, phase II study to evaluate the clinical benefit of maintenance niraparib in biomarker-defined, platinum-sensitive mCRPC patients. Eligible subjects harbor a pathogenic germline and/or somatic mutation in BRCA1/2, ATM, FANCA, CDK12, RAD51B, RAD54L, PALB2, CHEK2, HDAC2, or BRIP1 and have received at least 3 cycles (or minimum 9 weeks) of platinum-based chemotherapy for the treatment of mCRPC per investigator discretion. Following ³4 weeks since completion of chemotherapy, subjects without evidence of clinical or radiographic disease progression receive investigational treatment with maintenance niraparib (starting dose 200 mg daily). The primary objective is an improvement in 6 month PFS rate (PFS6) (H0: PFS6 rate 25%; H1: PFS6 rate 50%; power 0.77 with one-sided α = 0.05). Serial plasma samples are obtained for correlative analyses of markers of response and/or resistance to maintenance niraparib. Eight of a planned total of 18 subjects have enrolled (N=3 germline BRCA2; N=2 somatic BRCA2; N=1 germline PALB2; N=1 germline ATM; N=1 germline CHEK2). This study incorporates a novel, combined genetic and clinical patient-selection approach for PARPi therapy to optimize clinical outcomes. Clinical trial information: NCT04288687 .
Neo-adjuvant PARP inhibition prior to prostatectomy: A phase II biomarker-driven trial for men with high-risk, localized prostate cancer and alterations in DNA repair genes.
Authors: Dall'era Marc , McPherson John , Evans Christopher P. , Parikh Mamta , Verma Rashmi , Lara Primo N 
Published: March 2023

TPS401 Background: Many men with localized prostate cancer will experience recurrence and progression after radical prostatectomy. While radiation therapy for high-risk prostate cancer is routinely given with systemic androgen therapy, peri-operative systemic therapy is not part of the standard of care with prostatectomy. Defective DNA repair pathways represent a non-hormonal target for PARP inhibitors which have proven efficacy in the metastatic, castrate resistant setting. We designed a novel biomarker driven neoadjuvant trial with niraparib prior to prostatectomy for men with clinically localized high risk prostate cancer and alterations in DNA repair genes (NCT04030559). Methods: We instituted a phase II trial for men with NCCN high and very high-risk prostate cancer. All men who met inclusion by clinical variables underwent targeted genomic sequencing for somatic and/or germline alterations in genes involved in DNA repair pathways. Enrolled patients are treated with oral Niraparib 300mg/day for 90 days before surgery. The primary endpoint is pathologic response at prostatectomy defined as complete response or minimal residual disease (<0.5 cc3) of histological viable cancer. The secondary endpoint is biochemical free survival as well as molecular endpoints including disease responses stratified by mutational status. We have screened 37 men and 10 have met genomic criteria. We have enrolled 8 out of planned 30 men to date, 7 have undergone prostatectomy. Enrolled men have alterations in BRCA2 (germline), MSH6, ZMYM3, MUTYH, ATM, CDK12, ERCC3 and KMT2c. Clinical trial information: NCT04030559 .
A phase III randomized trial of eribulin (E) with or without gemcitabine vs standard of care (SOC) for metastatic urothelial carcinoma (UC) refractory to or ineligible for PD/PDL1 antibody (Ab): SWOG S1937.
Authors: Sadeghi Sarmad , Plets Melissa , Lara Primo N , Tangen Catherine , Bangs Rick , Lerner Seth P. , Flaig Thomas W. , Petrylak Daniel P. , Thompson Ian M 
Published: March 2023

TPS581 Background: UC is 2nd most common genitourinary cancer. Current SOC offers platinum-based (PB) first line chemotherapy (chemo) with ddMVAC or gemcitabine-cisplatin (GC) regimens. For cisplatin ineligible patients (pts), SOC includes gemcitabine-carboplatin (GCa), and in select pts pembrolizumab. Erdafitinib is approved for pts with FGFR alterations and Enfortumab vedotin (EV) is approved for previously treated pts. A phase I/II CTEP study of eribulin (E) for metastatic UC (mUC) established the activity of E in UC with objective response rate (ORR) of 37.5% and a median progression free survival (PFS) of 4.1 months (mo) and median overall survival (OS) of 9.5 mo (N=150). A phase II CTEP study of gemcitabine-eribulin (GE) in cisplatin ineligible mUC showed an ORR of 50%, median OS of 11.9 mo and median PFS of 5.3 mo (N=24). The most common Grade 3-4 toxicities included: neutropenia 63%, anemia and fatigue 29%. Pts with liver metastases benefited from therapy with 5 responders in 7 pts for GE vs 12 out 49 E. Methods: This is a phase III, randomized 3 arm study comparing E vs. GE vs. SOC (docetaxel, paclitaxel, or gemcitabine). E is given at 1.4mg/m2 on day (D) 1 and 8 of a 21 D cycle. In the GE arm, gemcitabine is added to E at 1000 mg/m2 dose to D1 and D8. SOC follows standard dosing of the agents. There is no limit to the number/sequence of prior regimens. A simplified summary of eligibility criteria is presented here. All pts must have: received frontline systemic treatment such as PB chemo or a non-platinum regimen; received PD1/PDL1 Ab or be deemed ineligible for PD1/PDL1 Ab; received EV. Assuming a median OS for the SOC arm of 7 mo the study seeks to find at least a 50% increase in median OS to 10.5 mo (Hazard Ratio (HR) = 0.667). One-sided 0.0125 type I error to account for testing of two primary hypotheses (Each arm vs. SOC). 87% power to detect a 3.5 mo improvement in OS. We require 140 eligible (155 total) pts in each arm for a total of 465. The study was activated in Feb 2021 and accrual is ongoing. Funding: National Institutes of Health/National Cancer Institute grants U10CA180888, U10CA180819. Clinical trial information: NCT04579224 .