bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enzalutamide versus abiraterone plus prednisolone before chemotherapy for Japanese castration-resistant prostate cancer patients: An investigator-initiated, multicenter, randomized controlled trial.
Authors: Izumi Kouji , Shima Takashi , Mita Koji , Kato Yuki , Kamiyama Manabu , Inoue Shogo , Tanaka Nobumichi , Hoshi Seiji , Okamura Takehiko , Yoshio Yuko , Enokida Hideki , Chikazawa Ippei , Kawai Noriyasu , Hashimoto Kohei , Fukagai Takashi , Shigehara Kazuyoshi , Takahara Shizuko , Kadono Yoshifumi , Mizokami Atsushi 
Published: February 2022

122 Background: Enzalutamide and abiraterone plus prednisolone demonstrated improvement of survival for castration-resistant prostate cancer (CRPC). However, it remains quite unclear which agent is better in terms of efficacy and safety for Asian patients. Methods: An investigator-initiated, multicenter, randomized controlled trial was conducted in Japan. CRPC patients before chemotherapy were randomly assigned to the enzalutamide or the abiraterone plus prednisolone arm (1:1). The primary endpoint is time to prostate-specific antigen (PSA) progression and secondary endpoints include PSA response rate (≥50% decline from baseline), overall survival, radiographic progression-free survival, and safety assessment. Results: Between February 20, 2015 and July 30, 2019, 203 patients were enrolled. After randomization, 92 in the enzalutamide and 92 in the abiraterone plus prednisolone arm were treated and analyzed. Time to PSA progression was not significantly different between arms (median 21.2 and 11.9 months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 0.81, 95% CI 0.51-1.27, p = 0.1732). There was a significant difference in PSA response rate between arms (72% and 57% in the enzalutamide and the abiraterone plus prednisolone arm, respectively, p = 0.0425). There were no significant differences in overall and radiographic progression-free survival between arms (median 32.9 and 35.5months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 1.17, 95% CI 0.72-1.88, p = 0.5290 and median 17.6 and 14.0 months in the enzalutamide and the abiraterone plus prednisolone arm, respectively; hazard ration 0.92, 95% CI 0.63-1.34, p = 0.6532). Grade ≥3 of adverse events were observed in 11% and 21% in the enzalutamide and the abiraterone plus prednisolone arm, respectively ( p = 0.1044). Conclusions: Enzalutamide did not show any survival benefits compared with abiraterone plus prednisolone but showed better PSA response rate with no significant differences of severe adverse event rate for Japanese CRPC patients. Our data suggest that antecedent use of enzalutamide to abiraterone plus prednisolone have potentially clinical benefits in Asian CRPC populations. Clinical trial information: UMIN000015529.
BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Carneiro Benedito A. , DeSouza Andre , Golijanin Dragan , Wood Roxanne , Olszewski Adam J , Holder Sheldon L. , El-Deiry Wafik S. , Aggarwal Rahul Raj , Mega Anthony E. 
Published: February 2022

128 Background: mCRPC with alterations in genes associated with homologous recombination (HR) DNA repair (e.g., BRCA1/2) is sensitive to poly ADP-ribose polymerase inhibitors (PARPi). Preclinical studies showed that PI3K inhibitors (PI3Ki) impairs HR and sensitize cancer cells to PARPi even in the absence of HR gene mutations. These results support our hypothesis that dual PI3K and PARP inhibition may improve clinical outcomes in progressive mCRPC. We describe preliminary results of a phase Ib/II study investigating safety of the combination of copanlisib (pan-class I PI3Ki) and rucaparib (PARP-1, -2 and -3 inhibitor). Methods: Enrollment criteria included progressive mCRPC, prior androgen inhibitors (abiraterone, enzalutamide, and/or apalutamide); prior taxane chemotherapy was allowed. HR-deficiency was not required for the phase Ib. The phase I followed a standard 3+3 escalation design. Dose schema: rucaparib (continuous oral administration twice daily) 400mg (dose level [DL] -1, 1), 500mg (DL 2) or 600mg (DL 3,4) and intravenous copanlisib (45mg D1, D15 (DL -1, -2); 45mg, D1, D8, D15 (DL 1, 2, 3); 60mg, D1, D8, D15 (DL 4); 28-day cycle). Adverse events (AE) were graded by CTCAE v5.0. The primary aim of the phase I was to establish the MTD and the recommended phase II dose (RP2D) of copanlisib in combination with rucaparib. Results: Eleven pts were enrolled with a median age of 63 (55-78) and median PSA of 12 ng/mL (0.018–2,101). Seven pts (63%) received prior chemotherapy (docetaxel [7], cabazitaxel [3]). Pathogenic HR mutations included BRCA1 (1), BRCA2 (3), CDK12 (1), and FANCA (1). Treatment-related AE included grade 2 (G2) leukopenia (30%), G2 anemia (20%), G2 rash (20%). Two dose-limiting toxicities (DLTs) were observed in DL 1: G3 rash and G3 AST/ALT elevation attributed to both drugs. Six pts were treated at DL -1 without DLTs. The RP2D was rucaparib 400mg BID with copanlisib 45mg (D1, D15; 28-day cycle). There were 2 confirmed PSA50 responses among 7 evaluable pts (28%). One pt had BRCA2 loss and 1 had PALB2 VUS (ongoing PSA response for 14 mo). Three stable disease and 1 partial response were observed among 6 pts evaluable by RECIST 1.1. Conclusions: The combination of rucaparib and copanlisib is well tolerated. The RP2D was rucaparib 400mg BID with copanlisib 45mg (D1, D15; 28-day cycle) with signal of efficacy. Enrollment in a phase 2 expansion cohort in HR-mutated mCRPC is ongoing. Clinical trial information: NCT04253262.
Association of RB1 mutational status with overall genomic landscape in neuroendocrine prostate cancer (NEPC).
Authors: Grivas Petros , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Necchi Andrea , Spiess Philippe E. , Danziger Natalie , Lin Douglas I. , Huang Richard S.P. , Parini Vamsi , Decker Brennan , Sokol Ethan , Tukachinsky Hanna , Levy Mia Alyce , Ross Jeffrey S. 
Published: February 2022

156 Background: NEPC is a high-grade aggressive form of prostate cancer. We queried whether RB1 mutation status would impact the genomic features of NEPC. We hypothesized that there would be differences in GA frequencies in RB1 mutated vs non mutated cases. Methods: From a series of 13,496 cases of clinically advanced PC, 415 (3.1%) histologically defined NEPC were sequenced using a hybrid capture-based FDA-approved clinical genomic profiling (CGP) assay to detect all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3) with low tumor cell positive staining 1-49% and high staining ≥50% expression. Results: 253 (61%) of NEPC feature GA in RB1 (RB1 mut+). This contrasts with a 5.8% frequency of RB1 GA in the non-NEPC (P <.0001). The RB1 mut+ NEPC featured a slightly greater number of driver GA/tumor than the RB1 mut- NEPC (5.1 vs 4.2). Age and TMPRSS2-ERG fusion frequency were similar between the groups. RB1 Mut- NEPC was associated with significantly higher amplifications (amp) and total GA in AR compared to RB1 mut+ NEPC. RB1 mut+ NEPC featured significantly greater frequency of PTEN GA. GA frequencies in targetable kinases and DNA repair GA including BRCA1/2 and ATM linked to PARP inhibitor (PARPi) response were similar in both groups. For potential immune-oncology (IO) biomarkers, RB1 Mut+ NEPC featured significantly greater frequency of low positive PD-L1 expression and lower frequencies of MDM2 and CDK12 GA. CD274 ( PD-L1) amplification, MSI-high status and cases with TMB ≥10 mut/Mb were very uncommon in both groups. Conclusions: In NEPC, the presence of RB1 mutation is associated with various GA that may have clinical relevance. Limitations include possible selection and confounding biases, and lack of clinical annotation. Further study of RB1 status as a guide of trial designs on therapy selection for men with NEPC is warranted.[Table: see text]
Health-related quality of life as a prognostic indicator of biochemical recurrence free survival in high-risk prostate cancer patients following radical prostatectomy.
Authors: Westhofen Thilo , Buchner Alexander , Schlenker Boris , Becker Armin , Stief Christian G. , Kretschmer Alexander 
Published: February 2022

235 Background: Several studies have shown baseline health-related quality of life (HRQOL) to be a valuable prognostic indicator of survival outcomes for various cancer entities in the metastatic setting. To date, there is no evidence regarding the prognostic value of baseline HRQOL for patients undergoing radical prostatectomy (RP) due to localized prostate cancer (PC). The objective of this study was to assess the impact of baseline preoperative HRQOL on survival prognosis for high-risk PC patients following RP. Methods: 1029 patients with high-risk PC according to NCCN risk stratification and prospectively assessed baseline HRQOL prior RP were included. Patients were stratified by the global health status (GHS) domain of the EORTC QLQ-C30 questionnaire, good general HRQOL was defined as GHS≥70 based on validated cut-off levels. Subsequently, a propensity score-matched analysis of 636 patients [n=318 (GHS≥70), n=318 (GHS<70)] was conducted. Primary endpoint was biochemical recurrence-free survival (BRFS), secondary endpoint was metastasis-free survival (MFS). Multivariate Cox regression models were performed to assess prognostic significance of baseline GHS on survival outcomes. Harrell’s discrimination C-index was applied to calculate the predictive accuracy of the model (p<0.05). Results: Median follow-up was 40mo. Applying matching variables age, PSA, pT stage, Gleason grade, positive surgical margin rate, and lymph node involvement, patients subcohorts were well-balanced. 5-yr-BRFS (61% vs. 28%; p<0.001) and 5-yr-MFS (86% vs. 68%; p=0.003) were significantly increased in the GHS≥70 cohort. In multivariate analysis GHS≥70 was confirmed as an independent predictor for increased BRFS (HR 0.60, 95%CI 0.44–0.82; p=0.013) and MFS (HR 0.51, 95%CI 0.30–0.87; p=0.026). Adding baseline HRQOL to our model improved predictive accuracy of BRFS by 8% (Harrell’s C-index of 0.69 vs 0.65). Conclusions: Our findings highlight baseline HRQOL to be a valuable and robust prognostic factor for patients with localized high-risk PC prior RP. Baseline good general HRQOL accurately predicts increased BRFS and MFS.[Table: see text]
Pathological and oncological outcomes of off-criteria radical prostatectomy in patients opting for active surveillance: From PRIAS-JAPAN.
Authors: Tohi Yoichiro , Kato Takuma , Nakamura Masaki , Matsumoto Ryuji , Sasaki Hiroshi , Mitsuzuka Koji , Inokuchi Junichi , Hashine Katsuyoshi , Yokomizo Akira , Kinoshita Hidefumi , Hara Isao , Kawamura Norihiko , Hashimoto Kohei , Inoue Masaharu , Teishima Jun , Kanno Hidenori , Fukuhara Hiroshi , Maruyama Satoru , Sakamoto Shinichi , Sugimoto Mikio ,   PRIAS-JAPAN
Published: February 2022

250 Background: Trigger for definitive treatment in active surveillance (AS) is strictly criteria-based, but some patients might be surgically treated without adherence to the criteria. We aimed to evaluate whether oncological outcomes differ depending on adherence to the criteria in patients who opting for AS. Methods: We retrospectively reviewed data of 1,035 patients enrolled in a prospective cohort of PRIAS-JAPAN. Of 162 patients underwent radical prostatectomy, 136 patients were analyzed, excluding those with Gleason score 3+4 at diagnosis, RP within one year of enrollment. Triggers for RP due to pathological reclassification on repeat biopsy was defined as on-criteria. We compared pathological findings on RP and prostate specific antigen (PSA) recurrence-free survival of on-criteria with off-criteria. Results: Off-criteria was 35 patients (24.7%). There were significant differences in the median time to RP (16 vs. 18.5 months, p<0.001) and median PSA before RP (6.1 vs. 8.3 ng/mL, p=0.007) when comparing patients with on-criteria and off-criteria. Fifty percent of off-criteria received RP within 35 months. On pathological findings of RP, pathological T3≤ (10.5 vs. 9.4%, p=0.183), Gleason score 4+3≤ (33 vs. 28.6%, p=0.679), and pathological N positive (4.3 vs. 0%, p>0.999) were not significantly different. At a median postoperative follow-up of 36 months, no significant difference in PSA recurrence-free survival was found (log-rank p = 0.828). Conclusions: Although half of off-criteria patients underwent RP within 3 years of starting AS, their oncological outcomes were not different from on-criteria. Our result suggested the potential for tailoring the inclusion criteria of AS within the strict protocol. Clinical trial information: 000002874. [Table: see text]
Real-world management of metastatic castration-resistant prostate cancer (mCRPC): A national multicenter cohort study.
Authors: Lavallee Luke , Morash Chris , Saad Fred , Yip Steven , Kapoor Anil , Kolinsky Michael Paul , Pouliot Frederic , Antebi Elie , Drachenberg Darrel , Ferrario Cristiano , Gotto Geoffrey , Hamilton Robert James , Ko Jenny J. , Noonan Krista , So Alan , Malone Shawn , Zardan Anousheh , Chi Kim N. , Hotte Sebastien J. , Niazi Tamim 
Published: February 2022

252 Background: The management of patients with mCRPC has evolved since the introduction of androgen-receptor axis targeted agents (ARATs). The Genitourinary Research Consortium (GURC) initiated a prospective, phase 4, multicentre, non-interventional, longitudinal cohort study of Canadian men with advanced prostate cancer to determine real-world treatment patterns and outcomes. Methods: 25 sites across Canada participated in this study including patients managed by urologists, medical- and radiation-oncologists between 2018 to 2021. Baseline patient characteristics and mCRPC treatment patterns are reported here. Treatment patterns reviewed included time to second-line treatment use and time to progression or death. Results: 136 mCRPC patients were enrolled. Median age was 73 years (range 66 to 80) with 54 (40%) having a Gleason score of >8 at diagnosis. Median PSA at enrollment was 8.9 (2.4 to 25.1) ng/ml. At study entry, 90/132 (66%) patients with mCSPC and 42/132 (31%) patients nmCRPC had progressed to develop mCRPC. One hundred and twenty-one (89%) of patients in this cohort received first-line treatment for mCRPC, the most common was abiraterone acetate + prednisone in 67 (49%) and enzalutamide in 41 (30%), followed by docetaxel in 6 (4.4%), and Radium-223 in 5 (3.7%) patients. During the 25-month median follow-up period (range 6-28), 59 (49%) of the patients receiving first line mCRPC therapy had documented disease progression or death. At the time of last recorded follow-up, 37 (28%) patients who progressed received a second-line therapy for mCRPC. Median time to progression in this cohort was 21 months (95% CI: 15.2 - NE), with ARAT-to-ARAT being the most common sequencing pattern observed in 15 (39%) patients, followed by ARAT to chemotherapy in 14 (37%). Conclusions: In this real-world analysis of mCRPC patients, ARAT therapy was the preferred approach for first-line treatment intensification in over 108 (80%) patients. Despite evidence of poor response rates, ARAT-to-ARAT was the most common sequencing for second line therapy, followed by ARAT-to-chemotherapy treatment. Further analysis and follow-up will help define optimal mCRPC management, in real world setting.
A phase I/II study of nivolumab and axitinib in patients with advanced renal cell carcinoma.
Authors: Zibelman Matthew R. , Carducci Michael Anthony , Ged Yasser , Molina Ana M. , Ravilla Rahul , Shaffer David R. , Lambert Courtney , Tafseer Mahvish , Basiura Rachel , Weismann Danielle , Kokate Rutika , Devarajan Karthik , Ruth Karen , Alpaugh R. Katherine , Anari Fern , Ghatalia Pooja , Geynisman Daniel M. , Plimack Elizabeth R. 
Published: February 2022

291 Background: Combination systemic therapy with tyrosine kinase inhibitors (TKIs) and an immune checkpoint inhibitor (IO) are an established standard of care for patients with metastatic renal cell carcinoma (mRCC). We performed a phase I/II study to investigate the safety and efficacy combining the TKI axitinib (axi) with the IO agent nivolumab (nivo). Methods: This phase I/II study investigated the combination of axi and nivo in an initial dose finding phase I portion with a 3+3 design to determine the recommended phase 2 dose (RP2D) of axi. The phase II portion included 2 parallel arms: treatment naïve mRCC patients and mRCC patients previously treated with TKIs alone or IO/IO combination (NCT03172754). We are presenting results from the treatment naïve arm only. Included patients had to have histology with any clear cell component, ECOG performance status of 0-1, no known or symptomatic brain metastases, and no history of autoimmune disease. The RP2D of axi was 5 mg BID from the phase I portion and patients could be treated for up to 2 years. The primary endpoint of the phase II portion was objective response rate (ORR) per investigator assessment. Results: Forty-four patients were accrued to the treatment naïve arm. One withdrew consent and was replaced but is included in the safety analysis, while 42 patients are evaluable for efficacy. The median age was 65 yrs (range: 42-84 yrs) and the group was predominantly male (83.7%) and white (95.3%). Using the IMDC risk group grading, 18 patients (41.9%) were favorable risk, 22 patients (51.2%) were intermediate risk and 3 patients (7 %) were poor risk. Median follow-up was 11.5 months. Best response data is shown in the table and is notable for an ORR of 69.0%, with only 1 patient (2.4%) experiencing primary progressive disease, for a disease control rate of 97.6%. Median progression free survival was 16.4 months (95% CI: 10.6 - 21.9 mo), and median overall survival (OS) was not reached. OS at 12 months was 86.7%. Adverse event (AE) data was similar to published data for IO/TKI combinations, with no grade 4-5 AEs. Twenty-nine patients experienced a grade 3 AE (70.7%), the most common of which was hypertension, and 14.0% discontinued the study due to treatment-related toxicity. Conclusions: The combination of axi/nivo for treatment naïve patients with mRCC demonstrated efficacy comparable to available IO/TKI combinations with a similar safety profile. Clinical trial information: NCT03172754. [Table: see text]
Factors associated with the quality of end-of-life care for patients with metastatic renal cell carcinoma.
Authors: Dzimitrowicz Hannah Elizabeth , Wilson Lauren E. , Jackson Bradford E. , Spees Lisa , Baggett Christopher , Greiner Melissa A. , Kaye Deborah , Zhang Tian , George Daniel J. , Scales Charles D. , Pritchard Jessica , Leapman Michael S. , Gross Cary Philip , Dinan Michaela Ann , Wheeler Stephanie B. 
Published: February 2022

300 Background: Although oral anti-cancer agents (OAAs) have improved outcomes for patients with metastatic renal cell carcinoma (mRCC), most patients still die from the disease. High quality end-of-life (EOL) care remains a crucial component of optimal care for patients with mRCC, but neither it nor systemic therapy use at EOL have been well characterized in these patients. Methods: We conducted a retrospective study of decedents with mRCC in 2 cohorts analyzed in parallel: 1) patients aged ≥18 years (diagnosed with RCC in 2004 through 2015) drawn from the University of North Carolina Cancer Information Population Health Resource (NC-CIPHR) and 2) patients aged ≥66 years (diagnosed with RCC in 2007 through 2015) from SEER-Medicare. OAA use was measured from date of mRCC diagnosis until 30 days prior to death. We assessed use of hospice in the last 30 days of life as well as established measures of low EOL care quality: receipt of systemic therapy, hospital admission, and ICU admission in last 30 days of life, and death in hospital. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence limits (95%CL) for associations between OAA use, patient and provider characteristics, and EOL care quality in both cohorts. Results: We identified 410 (NC-CIPHR) and 1508 (SEER-Medicare) patients with median ages of 69 and 75 years, respectively. 53.4% and 43.5% of decedents received an OAA in NC-CIPHR and SEER-Medicare, respectively. OAA use was associated with increased systemic therapy in the last 30 days prior to death in both datasets, increased hospice in the last 30 days prior to death in SEER-Medicare, and increased death in hospital in NC-CIPHR. OAA use was not associated with inpatient or ICU admission near EOL in both cohorts. Older patients were less likely to receive chemotherapy, be admitted, or die in the hospital near EOL in both cohorts. Dual-enrolled beneficiaries (Medicare and Medicaid) had decreased likelihood of hospice use in 30 days prior to death (OR = 0.71; 95%CL: 0.54, 0.94) and increased death in hospital (OR = 1.40; 95%CL: 1.02, 1.93) in SEER-Medicare. Conclusions: Patients with mRCC who received OAAs were more likely to receive systemic therapy at the EOL, however, they were also more likely to receive hospice care at EOL in the SEER-Medicare cohort with no differences in hospitalization near EOL. Future directions include characterization of EOL care in the era of immunotherapy treatments. [Table: see text]
Real-world assessment of changing treatment patterns and sequence for patients with metastatic renal cell carcinoma (mRCC) in the first-line (1L) setting.
Authors: Shah Neil J. , Sura Sneha , Shinde Reshma , Shi Junxin , Perini Rodolfo F. , Puneet Singhal , Robert Nicholas J. , Vogelzang Nicholas J. , Motzer Robert J. 
Published: February 2022

302 Background: Several immune-oncology (IO) agents and/or tyrosine kinase inhibitors (TKIs) have received approval for treatment of mRCC in 1L setting by Food and Drug Administration (FDA) over last few years. Limited data exists on evolving real-world treatment patterns and sequence in mRCC patients receiving these agents, especially at the community oncology setting. Methods: We used data from The US Oncology Network of over 1,300 providers from over 480 sites across United States from 01/01/2018 to 12/31/2020 (study period). Eligible study population included mRCC patients who received ipilimumab + nivolumab (Ipi+nivo) (IO+IO); pembrolizumab + axitinib (Pembro+axi) (IO+TKI); and axitinib (Axi) or cabozantinib (Cabo) or pazopanib (Pazo) or sunitinib (Suni) (TKIs monotherapy) in 1L setting until 09/30/2020. Descriptive statistics were used for cohort characterization. Results: We identified 3,756 mRCC patients, of which 1,538 were eligible including 42% (n=641) IO+IO, 18% (n=279) IO+TKI, and 40% (n=618) TKI monotherapy. The median age for the entire cohort was 67.1 years (range 25.0, 93.3), 70% (n=1,076) were male, 70% (n=1,081) were white, 38% (n=587) had BMI ≥ 30 and 79% (n=1,208) had clear cell histology. Among entire cohort, 87% (n=1,338) had intermediate/poor risk score as per International mRCC Database Consortium risk model. We noted a trend towards increased utilization of IO+IO and IO+TKI following their respective FDA approvals (IO+IO: April 2018, IO+TKI: April 2019) (Table). During the study period, overall, 35% (n=535), 12% (n=184), and 4% (n=62) mRCC patients received second-line (2L), third-line (3L) and fourth-line (4L) treatments, respectively. Cabo (49%) and pazo (12%); cabo (51%) and ipi+nivo (23%); and nivo (45%) and ipi+nivo (20%) were the most common 2L treatments in IO+IO, IO+TKI, and TKI monotherapy cohorts, respectively. Conclusions: This large real-world study examined use of new FDA approved mRCC treatments and their impact on treatment paradigm. The results show a rapid adaptation of these newer treatments in the community oncology settings. A longer follow-up is needed to assess their clinical impact and optimal treatment strategy in subsequent setting.[Table: see text]