bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I dose-escalation study of PSMA-targeted alpha emitter 225Ac-J591 in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tagawa Scott T. , Osborne Joseph , Fernandez Escarleth , Thomas Charlene , Niaz Muhammad Junaid , Ciriaco Amy , Vallabhajosula Shankar , Vlachostergios Panagiotis J. , Molina Ana M. , Sternberg Cora N. , Singh Sharon , Babich John , Nanus David M. , Ballman Karla V. , Bander Neil Harrison 
Published: May 2020

5560 Background: Antibodies (Abs) or small molecules can target PSMA with different biodistribution. Certain sites of PSMA expression (e.g. salivary/lacrimal glands, kidneys, small bowel) are not accessible to Abs. Given radiosensitivity of PC and potency of alpha emitters plus the ability to minimize targeting off tumor PSMA+ sites with J591, we performed a 1st in human study of 225Ac-J591. Methods: Men with progressive mCRPC following at least 1 potent AR-pathway inhibitor (ARPI) and chemo (or unfit/refuse) without limit of # prior therapies (Ra-223 and 177Lu-PSMA allowed) with ECOG PS 0-2 and adequate organ function were eligible. Baseline 68Ga-PSMA11 PET was performed, but not used for eligibility. Initially 1-subject cohorts treated until transition to 3+3 at dose level 5 (predicted by dosimetry to have moderate toxicity) with a single infusion of 225Ac-J591 (13.3 KBq/kg with planned escalation up to 93.3 KBq/kg). Dose-limiting toxicity (DLT) defined as attributable grade (Gr) 4 heme toxicity or Gr 3/4 non-heme tox. Imaging, genomic, patient-reported outcomes (PRO), and immune correlates embedded. Results: 22 men treated on 7 dose levels; median age 72.5 (range 58-89), PSA 147 (5-7168); 82% with >2 prior ARPI, 64% chemo, 23% Ra-223, 55% 177Lu-PSMA. 1 (5%) CALGB (Halabi) good prognostic risk, 10 (45%) intermed, 11 (50%) poor risk. 1 of 6 in cohort 6 (80 KBq/kg) had DLT (Gr 4 anemia and platelets); no others had attributable Gr > 2 non-heme or Gr > 3 heme AE (including 0 of 6 at the highest dose level 93.3 KBq/Kg). Gr 1/2 AE’s: 17 (77%) fatigue, 11 (50%) pain flare, 10 (45%) anemia (+1 Gr 3), 10 (45%) platelets, 6 (27%) nausea, 6 (27%) xerostomia (5 of 6 with prior 177Lu-PSMA), 5 (23%) neutropenia, 4 (18%) AST elevation. Despite prior treatment including 177Lu-PSMA and no selection for PSMA expression, 14 (64%) with any PSA decline, 9 (41%) with > 50% PSA decline. 15 (68%) had initial PSA rise followed by decline from peak (delayed effect). 2 with response > 1 year despite prior 177Lu-PSMA. Of 15 with paired baseline and 12-wk CTC counts, 8 declined, 4 remained undetectable, 3 increased. In subset with complete PRO data (baseline to 12 wks), pain was improved or absent by BPI-SF in 63% and by FACT-P in 89%. Social and emotional well-being domains of FACT-P improved or stabilized in majority; physical well-being improved in most responders. Conclusions: Alpha-emitter 225Ac targeting PSMA via J591 Ab is tolerable with early evidence of clinical activity in a pre-treated population with favorable PRO’s. Enrollment to expansion cohort being completed. Clinical trial information: NCT03276572 .
Results of the randomized phase II study of sipuleucel-T (Sip-T) +/- Radium-223 (Ra-223) in men with bone-metastatic castration resistant prostate cancer.
Authors: Marshall Catherine Handy , Park Jong Chul , Fu Wei , Wang Hao , DeWeese Theodore L. , King Serina , Afful Michaella , Hurrelbrink Julia , Manogue Charlotte , Cotogno Patrick , Moldawer Nancy P. , Barata Pedro C. , Drake Charles G. , Posadas Edwin Melencio , Armstrong Andrew J. , Sartor A. Oliver , Antonarakis Emmanuel S. 
Published: May 2020

5563 Background: It has been suggested that immune modulation can be augmented by radiation, possibly by enhancing tumor-antigen display. SipT-induced antigen-specific immune responses in mCRPC patients correlate with survival. We hypothesized that the combination of Ra223 and SipT would enhance SipT-related immune response and improve outcomes compared to SipT alone. Methods: Patients with asymptomatic, bone-predominant mCRPC, without visceral mets >1.0 cm, were randomized (1:1) to SipT alone or with 6 doses of Ra223 (NCT02463799). Men in the SipT+Ra223 arm started SipT between the 2nd and 3rd dose of Ra223. The primary immunologic endpoint was PA2024-specific T-cell proliferation 6 wks after the first SipT infusion. Secondary immune endpoints were PA2024-specific ELISPOT response, PAP-specific proliferation and ELISPOT, humoral responses against both antigens, and antigen spread. Clinical endpoints were radiographic PFS, PSA response (≥50% decline), AlkPhos response (≥30% decline), and safety. Results: 32 men were randomized, 16 per arm. Baseline characteristics in SipT+Ra223 and SipT arms were similar: age (median 71 vs. 70 yrs), Gleason (8-10: 69% vs. 69%), baseline PSA (med 25 vs. 33 ng/mL), AlkPhos (med 89 vs. 92 U/L) and ECOG score (≥1: 31% vs. 19%). There was no significant difference in prior use of abi/enza (38% vs. 44%), or chemo (0% vs. 25%). At 6 weeks, absolute PA2024-specific T-cell proliferation was 2.1-fold higher in the Sip-T arm compared to the SipT+Ra223 arm (35.6 vs. 16.6; P=0.03) and remained higher through week 26. Relative to baseline, the 6-week PA2024-specific T-cell proliferation change was 3.6 times greater in the Sip-T arm compared to the SipT+Ra223 arm ( P=0.007) and remained higher through week 14. There were no significant differences in antigen spread or humoral responses. Median radiographic PFS was longer in the SipT+Ra223 arm (9.3 vs. 3.2 months; HR 0.26, 95% CI 0.11–0.61; P=0.007). PSA and AlkPhos responses were better in the SipT+Ra223 arm (PSA50: 5/15=33% vs. 0/14=0%; P=0.04; AlkPhos30: 9/15=60% vs. 1/15=7%; P=0.01). There was no difference in SREs (13% vs. 7%). Conclusions: SipT+Ra223 was associated with improved clinical outcomes and a higher rate of PSA responses compared to SipT alone, although surprisingly, the SipT arm demonstrated higher peripheral PA2024-specific T-cell proliferation. Since neither agent reliably induces PSA responses alone, these data suggest a synergistic effect of the combination. Larger randomized studies of this combination are planned. Clinical trial information: NCT02463799 .
Safety and clinical activity of atezolizumab (atezo) + radium-223 dichloride (r-223) in 2L metastatic castration-resistant prostate cancer (mCRPC): Results from a phase Ib clinical trial.
Authors: Morris Michael J. , Fong Lawrence , Petrylak Daniel Peter , Sartor A. Oliver , Higano Celestia S. , Pagliaro Lance C. , Alva Ajjai Shivaram , Appleman Leonard Joseph , Tan Winston , Vaishampayan Ulka N. , Porcu Raphaelle , Tayama Darren , Kadel Edward Ernest , Yuen Kobe Chi Yung , Datye Asim , Armstrong Andrew J. 
Published: May 2020

5565 Background: mCRPC patients (pts) tend to have a poor prognosis and limited treatment (tx) options, especially those with concomitant bone metastases (mets). We explored the ability of combination tx with atezo (anti–PD-L1) and r-223 (α-particle emitter) to stimulate anti-tumor immunity in mCRPC pts. Methods: This Phase Ib study evaluated the safety and tolerability of atezo + r-223 in pts with mCRPC and multiple bone mets, visceral mets and/or lymphadenopathy who progressed after androgen pathway inhibitor tx. The initial cohort phase evaluated the safety and tolerability of a concurrent dosing schedule (CDS), in which atezo and r-223 were administered on the same day. Following assessment of CDS, pts were randomized 1:1:1 to CDS or 1 of 2 staggered dosing schedules (atezo or r-223 introduced a full cycle before the other). This was followed by an expansion of enrollment (randomized 1:1:1). Pts got atezo 840 mg IV q2w and r-223 at 55 kBq/kg IV 6 times at 4-wk intervals until unacceptable toxicity or loss of clinical benefit. Exploratory measures of efficacy included investigator-assessed ORR (RECIST 1.1), PSA response rate, time to PSA progression, radiographic PFS (rPFS; PCWG2 criteria) and OS. Biopsy samples were collected at baseline and prior to cycle 2 to evaluate changes in the tumor microenvironment during tx. Results: As of Oct 4, 2019, 45 pts were enrolled and 44 had evaluable data. Baseline characteristics were generally similar across groups. All 44 evaluable pts had ≥ 1 all-cause AE; 23 (52.3%) had Gr 3-4 AE. Eight pts (18.2%) had Gr 5 AE as per protocol reporting of deaths; 4 (9.1%) were from disease progression. Median follow-up was 13.9 mo (range, 1.7–34.2). Confirmed ORR was 6.8% (95% CI: 1.43, 18.66). Confirmed PSA response rate was 4.5% and median time to PSA progression was 3.0 mo (95% CI: 2.8, 3.3). Median rPFS was 3.0 mo (95% CI: 2.8, 4.6) and median OS was 16.3 mo (95% CI: 10.9, 22.3). Changes in PD-L1 and CD8 IHC were consistent with the known mechanism of action of atezo, as were changes in alkaline phosphatase with radium. Conclusions: No dose-limiting toxicities, safety signals, or changes in serum biomarkers were observed beyond the known safety profiles of atezo and r-223. This Phase 1b study did not seem to show clinical benefit from combination tx. Ongoing subgroup and biomarker analyses may provide additional insights. Studies of PD-1/PD-L1 targeted therapies in combination with tumor-directed radiation in molecularly selected mCRPC pts are planned or underway. Clinical trial information: NCT02814669 .
CARD: Overall survival (OS) analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel versus abiraterone or enzalutamide.
Authors: Tombal Bertrand F. , Castellano Daniel , Kramer Gero , Eymard Jean-Christophe , De Bono Johann S. , Sternberg Cora N. , Fizazi Karim , Wulfing Christian , Bamias Aristotelis , Carles Joan , Iacovelli Roberto , Melichar Bohuslav , Sverrisdottir Asgerdur , Theodore Christine , Feyerabend Susan , Helissey Carole , Poole Elizabeth , Ozatilgan Ayse , Geffriaud-Ricouard Christine , De Wit Ronald 
Published: May 2020

5569 Background: The CARD trial (NCT02485691) compared cabazitaxel vs. an androgen receptor targeted agent (ART; abiraterone/enzalutamide) in mCRPC previously treated with docetaxel and the alternative ART (abiraterone/enzalutamide), in any order. These post hoc analyses assessed OS from various time points and the impact of prognostic factors. Methods: Patients with mCRPC previously treated with docetaxel and progressing ≤ 12 months on prior abiraterone/enzalutamide were randomized 1:1 to cabazitaxel (25 mg/m2 IV Q3W + daily prednisone + prophylactic G-CSF) vs. abiraterone (1000 mg PO + daily prednisone) or enzalutamide (160 mg PO). OS was calculated from date of diagnosis of metastatic disease, date of mCRPC, and start of 1st, 2nd or 3rd life-extending therapy (LET). A stratified multivariate Cox regression analysis assessed the impact of 14 prognostic factors on OS using a stepwise model selection approach with a significance level of 0.10 for entry into the model and 0.05 for removal. Results: In the CARD study (N = 255), median OS was longer with cabazitaxel vs. abiraterone/enzalutamide (13.6 vs 11.0 months; HR 0.64, 95% CI 0.46–0.89; p = 0.008). OS was numerically improved for cabazitaxel vs. abiraterone/enzalutamide when assessed from the time of diagnosis of metastatic disease or mCRPC, or from start of 1st or 2nd LET (Table). In the multivariate analysis, low hemoglobin, high baseline neutrophil to lymphocyte ratio, and high PSA values at baseline were associated with worse OS. In presence of these factors, the OS benefit observed with cabazitaxel versus abiraterone/enzalutamide remained significant (HR 0.63, 95% CI 0.42–0.94, p = 0.022). Conclusions: Cabazitaxel numerically improved OS vs. abiraterone/enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative ART (abiraterone/enzalutamide), whatever the time point considered. The robustness of this OS benefit was confirmed by stratified multivariate analysis. Sanofi funded. Clinical trial information: NCT02485691 . [Table: see text]
Survival outcome in patients with metastatic castration-resistant prostate cancer according to first-line treatment.
Authors: Gross-Goupil Marine , Thurin Nicolas H. , Rouyer Magali , Jové Jérémy , Haaser Thibaud , Rebillard Xavier , Soulie Michel , de Pouvourville Gérard , Pierrès Marie , Capone Camille , Lamarque Stéphanie , Bignon Emmanuelle , Droz-Perroteau Cécile , Moore Nicholas , Blin Patrick 
Published: May 2020

5570 Background: Therapeutic strategy in metastatic castration-resistant prostate cancer (mCRPC) has evolved significantly with the introduction of abiraterone acetate in association with prednisone/prednisolone in first-line treatment in December 2012. This work aimed to compare the effectiveness of abiraterone acetate and docetaxel as first-line treatments for mCRPC, in real-life setting. Methods: Patients with mCRPC were identified in the main scheme of the National Healthcare System database (SNDS), which covers about 86% of the French population, and capturing all reimbursed healthcare expenditures and hospital discharge summaries. Those initiating docetaxel or abiraterone acetate in 1st line in 2014 were included and 1:1 matched on the previous prostate cancer stage before mCRPC status, the delay from the date of initial diagnosis and a high-dimensional propensity score. The 36-month overall survival and the 36-month discontinuation-free survival (i.e. survival time until treatment switch or death) were compared using Cox proportional hazards risk model. Results: In 2014, out of the 12,951 patients with prevalent mCRPC, 1,214 initiated docetaxel in 1st line and 2 444 initiated abiraterone. A total of 716 patients per group were matched with good comparability (C-statistic = 0.6). The median duration of docetaxel–defined as the time between the first and the last infusion–was 7.3 months with a median of 6 infusions. The median duration of abiraterone acetate–corresponding to the period covered by the dispensed drug–was 9.1 months. Near 70% of the docetaxel and 62% of the abiraterone acetate patients received a 2nd line of treatment. Results related to the main survival outcomes are presented in the table below. Conclusions: First-line treatment with abiraterone acetate in mCRPC patients results in a better 36-month overall survival and discontinuation-free survival compared to docetaxel in real-life setting. [Table: see text]
Quality of life (QOL) for the treatment sequence of abiraterone acetate plus prednisone (AAP) followed by enzalutamide (ENZ) versus the opposite sequence for metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized clinical trial.
Authors: Khalaf Daniel J , Sunderland Katherine , Eigl Bernhard J. , Finch Daygen L. , Oja Conrad D. , Vergidis Joanna , Zulfiqar Muhammad , Kollmannsberger Christian K. , Gleave Martin , Chi Kim N. 
Published: May 2020

5578 Background: A randomized cross-over phase II trial (Lancet Oncol 20(12):1730, 2019) showed the sequence of AAP followed by ENZ is associated with a better time to PSA progression compared with the opposite sequence and superior 2nd line activity of ENZ. It is unknown whether one treatment sequence is associated with better QOL than the other. Methods: 202 Patients were randomized (1:1) to receive either AAP followed by ENZ at PSA progression (arm A) or the opposite sequence of ENZ followed by AAP (arm B). FACT-P questionnaires were completed at baseline, cross-over and every 4 weeks on treatment. Time to QOL deterioration (TTQOLD) for the treatment sequence was determined from start of 1st line treatment to first questionnaire with a clinically meaningful decrease from baseline and compared between arms using the log-rank test. TTQOLD was also determined for 1st line and 2nd line separately. The proportion of patients with QOL deterioration for total FACT-P score and FACT-P subscores from baseline to week 12 of 1st and 2nd line treatment was compared between arms using X2 test. Results: Median follow-up for 1st and 2nd line and whole sequence were 9.3, 6.6 and 22.0 months (mos) respectively and questionnaire completion rate was 81%. TTQOLD for total FACT-P score for the whole sequence for arm A vs B was 10.5 mo (95% CI 5.0-15.5) vs 10.8 mo (5.5-13.1), p = 0.74. For 1st-line AAP vs ENZ, median TTQOLD was 15.5 mo (5.5-21.2) vs 11.0 (5.5-13.3) respectively (p = 0.23). For 2nd line ENZ vs ABI, median TTQOLD was 3.7 mo (2.0-5.4) vs 5.8 (2.8-12.1), p = 0.13. There was a higher rate of deterioration in physical well-being (PWB) for 1st line ENZ (arm B) and 2nd line ENZ (arm A) (Table). Conclusions: There was no difference in TTQOLD between the two treatment sequences of AAP and ENZ. Although treatment with second line ENZ has been associated with greater anti-cancer effects, ENZ was associated worse PWB QOL scores. Clinical trial information: NCT02125357 . [Table: see text]
Obesity and metabolic syndrome correlate with a higher risk of biochemical recurrence in high risk and intermediate risk prostate cancer patients who underwent robotic-assisted laparoscopic prostatectomy.
Authors: Mao Shifeng , Miller Ralph , Lyne John , Cohen Jeffrey , Samiei Arash 
Published: May 2020

5580 Background: Obesity and metabolic syndrome (MS) is prevalent in our society, and have been linked to a higher incidence of prostate cancer (PCa). The relationship of obesity or MS and cancer control has yielded mixed results in previous studies. We examined the correlation between the incidence of biochemical recurrence (BCR) with MS and BMI in a cohort of patients with PCa who underwent robotic-assisted laparoscopic prostatectomy (RALP). Methods: A retrospective study of patients who underwent RALP at a single center from 2007 to 2015 was conducted. Parameters including preoperative BMI, fasting glucose, lipid profile, blood pressure, PSA, Gleason score, pathologic stage, time to BCR, and surgical margin status were analyzed. Patients were categorized in high (HR), intermediate (IR), and low-risk (LR) groups based on the National Comprehensive Cancer Network (NCCN) guidelines. WHO classification was used for MS criteria, and BCR was defined as two consecutive postoperative PSA volume of ≥ 0.2 ng/mL. Obesity is defined as BMI ≥30 kg/m2. Results: A total of 726 patients with 189 in HR, 471 in IR and 66 patients in LR groups were included in this study with the median age of 59 (interquartile range [IQR] 55-64) years old. The median follow-up from surgery was 38 (IQR 22-46) months. More obese patients were found in the HR group compared to IR/LR group (46.5% vs. 33.1%, p<0.01). There were also more patients with MS in the HR group compared to IR/LR group (36.5% vs. 12.0%, p<0.01). Obese patients had a higher rate of BCR across risk groups in comparison to non-obese patients 32.1% vs. 15.4% (P<0.001), specifically 68% vs. 40%(p<0.01) in HR group and 21.3% vs. 12.7% (p=0.035) in the IR group. Similarly, patients with MS had a higher rate of BCR in HR and IR groups in comparison to the patients without MS, 39.1% vs. 18.7% (P<0.01); specifically, 67.7% vs. 42.2% (p<0.01) in HR and 29% vs. 11.6% (p<0.01) in the IR group. No correlation between MS or obesity and BCR was observed in LR group. There was no statistically significant difference in the positive surgical margin rate between obese and non-obese cohorts in each risk group. Conclusions: Among HR and IR-PCa patietns who underwent RALP, both obesity and MS correlate with increased risk of BCR. There were significantly more obesity and MS in HR-PCa patients, suggesting a potential pathophysiologic interplay between obesity or MS and cancer progression.
Cost-effectiveness of novel antiandrogens (AAs) for treatment of nonmetastatic castrate-resistant prostate cancer (nmCRPC).
Authors: Riaz Irbaz Bin , Almutairi Abdulaali , Lang Daenielle K. , Asghar Noureen , Riaz Anum , Yao Yuan , Sipra Qurat Ul Ain Riaz , Ryu Alexander J. , Alkhatib Nimer S , Oh Mok , Abraham Ivo , Murad M. Hassan , Kohli Manish 
Published: May 2020

5583 Background: FDA has approved three novel AAs [Apalutamide(A), Darolutamide(D) and Enzalutamide(E)] in combination with Androgen deprivation therapy ( ADT) for treatment of (nmCRPC) patients (pts). We report the cost-effectiveness of these drugs from the US perspective to help facilitate the choice of these agents for clinical practice. Methods: A life time Markov state-transition model was constructed with three health states (Metastasis-Free Survival[MFS], Metastatic disease, and Death) to compare cost-effectiveness of AA therapies for treatment of nmCRPC based on US healthcare payer perspective. A network meta-analysis of MFS and OS was conducted due to the lack of head to head trials. An approximation of the original individual-level patient time-to-event data were derived from digitized Kaplan-Meier curves for OS and MFS. Weibull distributions was selected as the best fitted model fitted and extrapolated as per the NICE decision support unit recommendations. Medication costs were based on wholesale acquisition cost. Adverse event (AE) grades 3/4 management costs were incorporated in the model. Discount rate of 3% per year was applied to costs and effects. Life years (LYs) and quality adjusted life years (QALYs) for each treatment as well as the incremental cost effectiveness (ICER) and cost utility (ICUR) ratios were estimated. Base case analyses (BCA) and probabilistic sensitivity analyses (PSA) were estimated. Results: The table summarizes the results form BCA analyses. A+ADT offers best gain in LYs (8.37yrs) and QALYs (5.30 yrs) but at higher cost. Conclusions: Apalutamide was associated with gains in LYs and QALYs traded off with higher lifetime cost relative to other AA alternatives. ADT was associated with lower gains in LYs and QALYs traded off with lower lifetime cost relative to other alternatives. Based on a $150,000/QALY threshold pay off, A+ADT is likely more cost effective compared to E+ADT or ADT alone; while E+ ADT may be more cost effective compared to D+ ADT. [Table: see text]