bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enzalutamide plus androgen deprivation therapy (ADT) versus flutamide plus ADT in men with castration-resistant prostate cancer (CRPC): AFTERCAB.
Authors: Uemura Hiroji , Kobayashi Kazuki , Yokomizo Akira , Hinotsu Shiro , Horie Shigeo , Kakehi Yoshiyuki , Naito Seiji , Nonomura Norio , Ogawa Osamu , Oya Mototsugu , Suzuki Kazuhiro , Saito Atsushi , Uno Satoshi , Akaza Hideyuki 
Published: March 2021

81 Background: Enzalutamide has been approved for the treatment of CRPC in Japan since 2014. This study compared the efficacy and safety of enzalutamide + ADT and flutamide + ADT in the treatment of men with CRPC who progressed despite combined androgen blockade with bicalutamide + ADT. The sequential order of treatment was also investigated. Methods: The open-label, Phase 4 AFTERCAB study (NCT02918968) was conducted from November 2016–March 2020 in Japanese men aged ≥20 years with asymptomatic or mildly symptomatic CRPC (metastatic or nonmetastatic) and an Eastern Cooperative Oncology Group performance status of 0 or 1 who progressed despite bicalutamide + ADT. Patients were initially randomized to enzalutamide (160 mg/day) + ADT (enzalutamide first) or flutamide (375 mg/day [125 mg 3 × daily]) + ADT (flutamide first) as first-line therapy. Following prostate-specific antigen (PSA) progression, other disease progression, or discontinuation of first-line therapy due to an adverse event (AE), patients switched to the other treatment as second-line therapy. The primary endpoint was time to PSA progression with first-line therapy (TTPP1). Secondary endpoints included TTPP2 (TTPP1 + time to PSA progression with second-line therapy). AEs were monitored to assess safety. Results: 206 men were randomized, stratified by study site and disease stage. Baseline demographics and disease characteristics were similar between treatment arms. Median treatment exposure was 14.3 months (range 0.8–35.9) with enzalutamide first and 5.6 months (range 0.3–37.7) with flutamide first. 133 patients transitioned to second-line therapy (n=48 for enzalutamide first and n=85 for flutamide first). TTPP1 was significantly improved with enzalutamide first versus flutamide first; numerically longer TTPP2 was observed with enzalutamide first versus flutamide first (Table). With first-line therapy, 92.2% (n=94) of patients reported treatment-emergent AEs (TEAEs) and 28.4% (n=29) reported serious TEAEs for enzalutamide first. Corresponding numbers for flutamide first were 76.0% (n=79) for TEAEs and 14.4% (n=15) for serious TEAEs. Conclusions: Treatment with enzalutamide + ADT provided a significant improvement in time to PSA progression versus flutamide + ADT as first-line therapy. Both treatments were generally well tolerated, with AEs consistent with the known safety profiles. Clinical trial information: NCT02918968. [Table: see text]
Efficacy of the PD-L1 inhibitor avelumab in neuroendocrine or aggressive variant prostate cancer: Results from a phase II, single-arm study.
Authors: Brown Landon Carter , Halabi Susan , Humeniuk Michael Sandon , Wu Yuan , Oyekunle Taofik , Huang Jiaoti , Anand Monika , Davies Catrin , Zhang Tian , Harrison Michael Roger , George Daniel J. , Armstrong Andrew J. 
Published: March 2021

89 Background: Men with metastatic neuroendocrine/small cell and aggressive variant prostate cancer (NEPC/AVPC) have poor outcomes despite platinum and taxane chemotherapy. These tumors share common features with small cell lung cancer, including higher tumor mutational burden and genomic alterations, and thus may be responsive to immunotherapy. Methods: We conducted a single arm, 2-stage phase II investigator-sponsored trial, (PICK-NEPC, NCT03179410) with the PD-L1 inhibitor avelumab in patients with NEPC/AVPC. NEPC/AVPC was defined either by histologic criteria (neuroendocrine or small cell features) by central pathology review or by aggressive variant clinical criteria (prior progression on abiraterone or enzalutamide with liver metastasis, bulky radiographic progression and low PSA, or high serum LDH). Prior chemotherapy or hormonal therapy was allowed. Avelumab 10 mg/kg IV every 2 weeks was administered until progression or unacceptable toxicity with ongoing ADT. The primary endpoint was overall response rate (ORR) defined by modified PCWG3 and iRECIST criteria. Results: We consented 19 men with AVPC/NEPC, and 15 initiated treatment with avelumab. The median age was 71 (range 51-85), and 27% had neuroendocrine or small cell histology, while 73% met AVPC clinical criteria with adenocarcinoma histology. Men had received a median of two prior systemic therapies (range 1-3) including carboplatin (27%), docetaxel (73%), enzalutamide (67%), and abiraterone (47%). Median PSA was 54 ng/mL (range 0-393) and 73% had liver metastasis. The ORR by iRECIST was 6.7% (95% CI 0-32%) with 1 CR, 0 PRs, 3 (20%) with stable disease, and 11 (73%) with progressive disease. The patient with a CR had NEPC with a CNS metastasis that was found to be MSI-high/TMB-high due to a somatic MSH2 alteration; he finished 12 months of avelumab and maintains a durable CR and undetectable PSA 6 months after completing all therapy including ADT. Median radiographic progression free survival was 1.8 months (95% CI 1.6-2.0 mo) and median time on therapy was 56 days (range 28-356). Median overall survival was 7.4 mo (85% CI 2.8-12.5 mo). Two grade 3 adverse events (abdominal pain due to hepatic disease progression versus immune hepatitis and pericarditis), and one grade 4 (immune hepatitis) adverse event were attributed to avelumab with no grade 5 adverse events. Grade 1 or 2 infusion-related reactions were experienced by 9 (60%). Conclusions: PD-L1 inhibition with avelumab demonstrated limited clinical efficacy in men with metastatic NEPC/AVPC other than in those with MSI-high disease. Further research is needed into mechanisms of immune evasion in NEPC/AVPC to develop novel immunotherapies. Clinical trial information: NCT03179410.
Anaplastic features (AnaF) and DNA-damage repair pathway (DDR) mutations in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Chau Vincent , Madan Ravi Amrit , Bilusic Marijo , Cordes Lisa M. , Marte Jennifer L. , Owens Helen , Hankin Amy , Gulley James L. , Lee Jung-Min , Dahut William L. , Karzai Fatima 
Published: March 2021

92 Background: Anaplastic prostate cancer displays features of small-cell carcinoma, a type of neuroendocrine tumor. Treatments for anaplastic prostate cancer are based on small cell lung cancer regimens. Both AnaF and mutations in DDR pathways, including BRCA2 confer an aggressive phenotype. For patients (pts) with certain DDR mutations, olaparib (O) was recently FDA approved, and an ongoing study is evaluating whether the addition of durvalumab (D) confers additional benefit in mCRPC (NCT02484404). We evaluate a potential preliminary relationship between DDR mutations, treatment with D and O, and AnaF. Methods: This is a phase II study of O plus D in pts with mCRPC with disease that is amenable to biopsy. On-study core biopsies undergo mutational analysis. Prior treatment with enzalutamide (enza) and/or abiraterone (abi) is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Pts were categorized into those with and without AnaF as defined by Aparicio et al. (2013). AnaF include small-cell histology; exclusively visceral metastases; predominantly lytic bone metastases; bulky lymphadenopathy (≥5 cm) or high-grade (Gleason ≥8) mass in prostate/pelvis; low PSA (≤10 ng/mL) at initial presentation with high volume (≥20) bone metastases; neuroendocrine markers in histology or serum plus elevated LDH, malignant hypercalcemia, or elevated serum CEA; or short interval (≤6 months) to androgen-independent progression. Results: Of 55 pts accrued, 24 had prior abi and enza; 19 pts had prior taxane. Common adverse events include anemia, fatigue, and nausea. Also, 11 pts (20.0%) displayed clear AnaF (Table) and 43 pts lacked AnaF, including 8 (14.5%) with partial AnaF that did not meet the full criteria, 4 (7.3%) who likely did not have AnaF due to difficulty in quantifying disease burden, 29 (52.7%) who did not have AnaF, and 2 (3.6%) had unknown status. Four pts (36.4%) with clear AnaF had DDR aberrations, including 3 (27.3%) with BRCA2, 1 (9.1%) with both BRCA2 and CHEK2, and 1 (9.1%) with ATM. Conclusions: Pts with mCRPC with DDR mutations can also have AnaF. This preliminary data demonstrates that pts with anaplastic prostate cancer and pts with DDR mutations are two distinct populations with some degree of overlap. O+D is well-tolerated, and future studies should focus on finding optimal treatments for pts with AnaF without and without DDR mutations. Clinical trial information: NCT02484404. [Table: see text]
Phase I study of entinostat in combination with enzalutamide for treatment of patients with castration-resistant prostate cancer.
Authors: Lin Jianqing , Elkon Jacob Matt , Ricart Brittany , Burgess Brooke , Palmer Erica , Siegel Robert S. , Ma Yan , Villagra Alejandro 
Published: March 2021

96 Background: Entinostat (SNDX-275, MS-275) is an oral histone deacetylase (HDAC) inhibitor with selectivity towards class I and IV HDACs. Entinostat inhibits prostate cancer (PCa) growth and suppresses Treg cell function in vitro and in vivo. The primary objective of this study was to determine the safe dose of Entinostat in combination with Enzalutamide in prostate cancer patients (PCa). Methods: Phase I, 2 cohorts "3+3", dose-escalation study to explore the safety and preliminary efficacy of Entinostat in combination with Enzalutamide in castration-resistant PCa (CRPC). The planned dose level of Entinostat was 3 and 5 mg orally per week. CRPC Patients progressed on Enzalutamide or eligible for Enzalutamide, able to tolerate 160 mg daily dose (in the initial run-in phase if Enzalutamide naïve), ECOG 0-1, and acceptable organ functions were enrolled in the study. The safety profile of the combination therapy, PSA, pharmacokinetics of Enzalutamide post-Entinostat administration, and peripheral T cell subtype (including Treg), mononuclear cell (PBMC) histone 3 acetylation were analyzed. Results: Total 6 mCRPC patients were enrolled. There was no dose limiting toxicity related to Entinostat in these patients. No obvious increased fatigue related to Entinostat. Toxicities possibly or probably related to Entinostat or the combination therapy included G3 anemia 1/6 (17%), G2 WBC decrease 1/6 (17%), All other toxicities were grade 1 only (Nausea 2/6, anorexia 1/6, emesis 1/6, constipation 1/6, headache 1/6, platelet count decrease 1/6, hypokalemia 1/6, hypoalbuminemia 1/6, hypermagnesemia 1/6). The median duration of treatment with Entinostat was 18 weeks. For patients already progressed on Enzalutamide there was no PSA response after Entinostat was added. Entinostat did not affect the steady plasma concentration of Enzalutamide. Increased PBMC H3 acetylation was observed (up to 3.6 fold from baseline) in the tested samples. No evident T cell subtype, including Treg, changes from these sample analysis. Phase II part of the trial was terminated because of sponsor withdrawal. Conclusions: Entinostat at the selected dose levels in combination with standard dose of enzalutamide showed promising safety profile in this small phase I study. Clinical trial information: NCT03829930.
18F-fluciclovine positron emission tomography (PET) in metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate.
Authors: Barata Pedro C. , Manogue Charlotte , Jaeger Ellen , Light Malcolm , Cotogno Patrick , Ledet Elisa Marie , Goffin Janeiro , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver 
Published: March 2021

TPS171 Background: Conventional imaging of prostate cancer has limitations in staging, restaging after biochemical relapse, and response assessment. Functional imaging with positron emission tomography (PET) can target various aspects of tumor biology and has shown to be superior in the detection of prostate cancer compared with conventional computed tomography (CT) and bone scans. 18F-Fluciclovine, a synthetic amino acid transported across mammalian cell membranes by amino acid transporters that is upregulated to a greater extent in prostate cancer cells than in surrounding tissue, is currently approved for PET imaging for patients with biochemical recurrence. The role of 18F-Fluciclovine PET scans in monitoring response to novel hormonal therapies such as abiraterone acetate is unclear. We hypothesize that 1) using 18F-Fluciclovine PET scanning will allow a more sensitive assessment of mCRPC patients at the initiation of systemic therapy with abiraterone acetate and 2) the changes observed in 18F-Fluciclovine PET will correlate better with the serologic changes in PSA, allowing superior disease monitoring, than conventional imaging modalities. Methods: This single-arm, pilot study (NCT04158245) will describe the changes in 18F-Fluciclovine PET scan and compare these results with PSA and conventional computerized tomography (CT) and bone scans, in mCRPC patients treated with abiraterone acetate plus prednisone. Patients must have a detectable baseline PSA of ≥ 2 ng/mL and metastatic disease detected on conventional CT and bone scans. The use of docetaxel in the hormone-sensitive setting is allowed. Twelve patients will be treated with abiraterone 1000 mg daily plus prednisone 5 mg (or dexamethasone 0.5 mg) daily for mCRPC and get 18F-Fluciclovine PET and conventional CT and bone scans at baseline and 12 weeks after starting abiraterone therapy or at disease progression. PSA progression will be defined as a repeated increase in PSA of at least 2 ng/dL and 25% from nadir values, at least 1 week apart, according to PCWG3 criteria and clinical or radiographic progression by RECIST version 1.1. The co-primary objectives of the study include the 18F-Fluciclovine PET changes at baseline and 12 weeks after abiraterone acetate for mCRPC and the comparison between 18F-Fluciclovine PET and conventional scans. Secondary and exploratory endpoints include PSA response, PSA progression and genomic alterations by next-generation sequencing. As of 12 September 2020, this trial is actively enrolling. Clinical trial information: NCT04158245.
Treatment of aggressive prostate cancers in real life: Initiation, schedule, and management of triptorelin treatment (TALISMAN)—Design of the study.
Authors: Lebret Thierry , Rigaud Jerome , Crehange Gilles , Pello Leprince Ringuet Nathalie , Grandoulier Anne-Sophie , Thiery-Vuillemin Antoine 
Published: March 2021

TPS173 Background: Prostate cancer (PCa) treatment management mostly depends on tumor aggressiveness and patient frailty. Guidelines recommend an intensification of treatment in high risk PCa, with a longer duration of androgen deprivation therapy (ADT), and, for more advanced cases, an administration for life, on top of which additional treatments may be proposed. This implies a holistic management of the patient, including management of comorbidities and ADT side effects. Triptorelin is a widely used gonadotropin-releasing hormone agonist (GnRHa). Generating data on the use of triptorelin in real life will help physicians to analyze the parameters influencing the choice of the planned duration of treatment. Methods: This prospective, multicenter, non-interventional study is conducted in France. Patients are recruited by urologists, radiation oncologists and medical oncologists. Main inclusion criteria are a histologically confirmed PCa, eligible for triptorelin therapy in its label, with a planned total duration of triptorelin treatment of at least 12 months. Decision of triptorelin treatment is made before the inclusion in the study, in the routine practice. 3 visits are planned: V1 (baseline), V2 (at 6 months), V3 (at 12 months). Primary objective of the study is to describe the proportion of patients treated continuously with triptorelin during 12 months following treatment initiation. 786 patients are planned to be enrolled, this will allow to estimate the proportion of patients treated continuously with triptorelin during 12 months following treatment initiation for an expected proportion of 80% with a precision of 3 % taking into account a drop out rate of 15%. Main secondary objectives are to describe the planned total duration of triptorelin treatment and main reason of choice, to identify parameters (tumor aggressiveness criteria, patient frailty...) associated with this planned duration, to describe the formulation and route of administration of triptorelin and reasons of choice, to identify parameters associated with this choice, to describe the change from baseline in quality of life evaluated through QLQ-PR25 questionnaire, and to describe the safety of triptorelin in the real world setting. An interim analysis on baseline data will be performed once 50% of patients are enrolled. It will focus on planned total duration of triptorelin at initiation, main reasons of choice according to circumstances of prescription, formulation and route of administration, and their reasons of choice. Clinical trial information: NCT04593420.
Study of the dosimetry, safety, and potential benefit of 177Lu-PSMA-617 radionuclide therapy prior to radical prostatectomy in men with high-risk localized prostate cancer (LuTectomy study).
Authors: Alghazo Omar , Eapen Renu , Dhiantravan Nattakorn , Violet John A. , Jackson Price , Scalzo Mark , Keam Simon P. , Mitchell Catherine , Neeson Paul J. , Sandhu Shahneen Kaur , Williams Scott , Moon Daniel , Lawrentschuk Nathan , Azad Arun , Hofman Michael S , Murphy Declan G. 
Published: March 2021

TPS264 Background: High-risk localised prostate cancer (HRCaP) is treated by radical prostatectomy (RP) or radiotherapy. Despite curative intent, a significant number of men will progress with metastatic disease or local recurrence. Lutetium-177 radiolabelled to the small molecule PSMA-617 targeting prostate-specific membrane antigen (Lu-PSMA) has proven efficacious in men with metastatic castration-resistant prostate cancer who have progressed after standard-of-care. The LuTectomy trial evaluates whether administration of Lu-PSMA before radical prostatectomy in men with HRCaP will deliver high doses of radiation to the prostate and involved lymph nodes. It also aims to assess the feasibility, safety profile and oncological efficacy of Lu-PSMA. Methods: Lutectomy is an open-label, phase I/II non-randomised clinical trial. 20 men with HRCaP defined by European Association of Urology who are scheduled for RP and pelvic lymph node dissection (PLND) will be recruited. All men will have high PSMA-avidity with a standardised uptake value (SUVmax) of ≥ 20 on 68Ga-PSMA PET/CT. The initial 10 participants will receive one cycle of 5GBq Lu-PSMA intravenously and the latter 10 men will receive two cycles of 5GBq Lu-PSMA per cycle six weeks apart. RP with PLND will be performed six weeks later. Participants will be followed up for three years. The primary outcome is to determine the radiation absorbed dose in the prostate and involved lymph nodes. Three-time point quantitative single-photon emission computed tomography (SPECT/CT) will be used to estimate radiation dosimetry using a voxelated technique incorporating partial volume correction. Marrow absorbed dose will also be evaluated using serial blood measures to model pharmacokinetic clearance with a multi-phase exponential model. Translational research samples will include the original biopsy, prostatectomy specimen and plasma/whole blood samples. Secondary objectives include evaluation of the PSMA PET/CT imaging response (defined by SUVmax decline >30%), PSA response, pathological response following Lu-PSMA, adverse effects of Lu-PSMA, surgical safety, and health-related quality of life. Post estimates for time-to-event endpoints will be estimated using the Kaplan-Meier method. The first patient was recruited in July 2020 and recruitment is expected to take up to two years. ClinicalTrials.gov Identifier: NCT04430192. Funding: Movember and Medical Research Future Fund (MRFF), Endocyte Inc., a Novartis Company, E.J. Whitten Foundation. Clinical trial information: NCT04430192.
CONTACT-03: Randomized, open-label phase III study of atezolizumab plus cabozantinib versus cabozantinib monotherapy following progression on/after immune checkpoint inhibitor (ICI) treatment in patients with advanced/metastatic renal cell carcinoma.
Authors: Pal Sumanta K. , Albiges Laurence , Suarez Rodriguez Cristina , Liu Bo , Doss Jennifer , Khurana Sudha , Scheffold Christian , Voss Martin H , Choueiri Toni K. 
Published: March 2021

TPS370 Background: Combining anti-angiogenic drugs with immune checkpoint inhibitors (ICI) after progression on ICIs presents a promising therapeutic approach in renal cell carcinoma (RCC). Atezolizumab (anti-PD-L1 mAb) has shown activity in combination with anti-angiogenic therapy after prior progression with ICI. Cabozantinib (VEGFR-TAM-TKI), a standard of care therapy in RCC, promotes an immune-permissive environment and may enhance atezolizumab activity. In phase Ib COSMIC-021, cabozantinib + atezolizumab safety and efficacy was favorable in clear-cell(cc) RCC and non(n)-ccRCC (Pal et al [702O] and McGregor et al [709P], ESMO 2020). The phase III CONTACT-03 study is further evaluating cabozantinib + atezolizumab vs cabozantinib in second-line/third-line RCC after prior ICC therapy. Methods: CONTACT-03 (NCT04338269) is a phase III, open-label, randomized, multicenter study that will enroll ≈500 patients across more than 150 sites globally. The trial opened in July 2020 and is actively recruiting adult patients with RCC. Key inclusion criteria include histologically confirmed locally advanced or metastatic ccRCC or nccRCC (papillary or unclassified); radiographic disease progression during or following first-line/second-line ICI treatment; measurable disease (RECIST 1.1); KPS score ≥70%; and availability of an archival tumor specimen and fresh biopsy (if clinically feasible). Patients must have adequate hematological and end organ function. Prior ICI therapy must be a PD-1/PD-L1 inhibitor (mono- or combination therapy) and must be in the immediate preceding line of therapy. Key exclusion criteria include prior treatment with cabozantinib or a mTOR inhibitor. Patients with symptomatic, untreated, or actively progressing CNS metastases or significant other intercurrent illness are not eligible. Stratification factors are IMDC risk group (0 vs 1-2 vs ≥3); line of most recent prior ICI therapy (first vs second); and histology (dominant cc without sarcomatoid vs dominant non-cc [papillary or unclassified] without sarcomatoid vs any sarcomatoid component [cc or ncc]). Patients will be randomized 1:1 to receive atezolizumab (1200 mg/IV/q3w) plus cabozantinib (60 mg/oral/qd) or cabozantinib alone (60 mg/oral/qd) until unacceptable toxicity or loss of clinical benefit. Patients will not be allowed to crossover from the control arm to the experimental arm. Multiple primary endpoints are independent review facility (IRF)-assessed PFS and OS. Additional endpoints include investigator-assessed PFS, IRF- and investigator-assessed ORR and DOR; HRQOL, biomarkers and safety. Radiographic efficacy will be assessed per RECIST 1.1. Clinical trial information: NCT04338269 .