bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictors of falls and fractures in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with apalutamide (APA) plus ongoing androgen deprivation therapy (ADT).
Authors: Pollock YaoYao Guan , Smith Matthew Raymond , Saad Fred , Chowdhury Simon , Oudard Stephane , Hadaschik Boris A. , Olmos David , Mainwaring Paul N. , Lee Ji Youl , Uemura Hiroji , Bhaumik Amitabha , Londhe Anil , Rooney Oliver Brendan , Lopez-Gitlitz Angela , Mundle Suneel , Cheng Shinta , Small Eric Jay 
Published: May 2019

5025 Background: SPARTAN, a phase 3 study of APA vs placebo (PBO) added to ongoing ADT in pts with nmCRPC, demonstrated that APA significantly prolongs metastasis-free survival, time to symptomatic progression, and second progression free survival (Smith et al. NEJM 2018), with no decline in health-related quality of life (Saad et al. Lancet Oncol 2018). SPARTAN pts who received APA, vs PBO, with ongoing ADT had higher rates of falls (15.6% vs 9.0%) and fractures (11.7% vs 6.5%). An analysis was performed to identify clinical characteristics associated with falls and fractures in APA-treated SPARTAN pts. Methods: Of 1207 pts enrolled, 806 were randomized to APA. Univariate Cox proportional hazards model (UVA) assessed the association of 47 baseline clinical characteristics (demographics, comorbidities, and medication use, including bone-sparing agents) with time to fall or time to fracture. Characteristics with p values < 0.10 were included in a multivariate Cox proportional hazards model (MVA) to determine independent factors associated with these outcomes (p < 0.05). Results: Factors associated with time to both fall and fracture on UVA (p < 0.10) included older age, low serum albumin, and poor ECOG performance status (PS). Additional factors associated with time to fall were cerebrovascular accidents/transient ischemic attacks, neuropathy, depression, α-blocker use, and antidepressant use. On MVA, older age, poor ECOG PS, history of neuropathy, and α-blocker use were independently associated with falls; older age and low serum albumin were independently associated with fractures (Table). Conclusions: At initiation of APA added to ongoing ADT, nmCRPC pts with higher risk of falls and fractures can be identified and are candidates for intervention to reduce the risk for these events. Clinical trial information: NCT01946204. [Table: see text]
Platinum-based chemotherapy in metastatic prostate cancer with alterations in DNA damage repair genes.
Authors: Mota Jose Mauricio , Barnett Ethan , Nauseef Jones , Stopsack Konrad Hermann , Wibmer Andreas Georg , Danila Daniel Costin , Rathkopf Dana E. , Slovin Susan F. , Kantoff Philip W. , Scher Howard I. , Morris Michael J. , Solit David B. , Abida Wassim 
Published: May 2019

5038 Background: Platinum-based chemotherapy has shown palliative and radiographic benefit in small unselected studies of metastatic castration-resistant prostate cancer (mCRPC). Alterations in DNA damage repair genes (DDRmut), which occur in ~25% of patients with mCRPC, may sensitize to platinum-based chemotherapy, and may aid in the selection of patients for this therapy. We sought to evaluate the efficacy of platinum-based chemotherapy in DDRmut mCRPC. Methods: We performed a retrospective review of patients with prostate cancer who underwent tumor genomic profiling and received platinum-based chemotherapy. Deleterious alterations in a panel including BRCA2, BRCA1, ATM, FANCA, CDK12 or PALB2 were classified as DDRmut. Absence of deleterious alterations in those genes was classified as DDRwt. MSI-H cases were excluded from analysis. Electronic charts, PSA values, and scans were reviewed to assess for outcomes. Results: From October 2013 to July 2018, 109 patients with mCRPC received platinum-based chemotherapy. 64/109 had prior taxane progression and were PARP inhibitor (PARPi) naïve at the time of platinum-based chemotherapy. DDRmut was found in 16/64 (25%) of patients ( BRCA2, n = 6; ATM, n = 2; CDK12, n = 4; FANCA, n = 4; PALB2, n = 1). Visceral metastasis occurred in 4/16 (25%) of DDRmut patients and in 22/48 (46%) of DDRwt patients. PSA50 responses were more common among DDRmut (8/15 evaluable = 53%, 95% CI, 30-75%) than among DDRwt patients (5/42 evaluable = 12%, 95% CI, 5-25%). Time on platinum-based chemotherapy tended to be longer in the DDRmut group (median 3.1 vs 1.8 months; HR 0.73, 95% CI 0.42-1.26). Of 8 DDRmut patients ( BRCA2, n = 6; BRCA1, n = 1; ATM, n = 2) who received platinum-based chemotherapy after progression on a PARPi, 3/7 evaluable patients (43%) had RECIST response or stable disease, and 2/7 evaluable patients (29%) had a PSA50 response. Of 4 patients with ATM deleterious mutations, none had a radiographic or PSA50 response to platinum-based chemotherapy. Conclusions: Platinum-based chemotherapy showed activity in DDRmut mCRPC patients before and after PARPi treatment.
A phase II multicenter biomarker trial to study the predictive value of TMPRSS2-ERG before enzalutamide treatment in chemo-naïve metastatic castration-resistant prostate cancer.
Authors: Grande Enrique , Fernandez Perez Maria Piedad , Wetterskog Daniel , Font Pous Albert , Vazquez-Estevez Sergio , Gonzalez del Alba Aránzazu , Mellado Begona , Fernandez Calvo Ovidio , Mendez-Vidal Maria Jose , Climent Miguel Ángel , Duran Ignacio , Gallardo Diaz Enrique , Rodriguez Sanchez Angel , Santander Carmen , Sáez M Isabel , Puente Javier , Castro Elena , Castellano Daniel E. , Attard Gerhardt , González-Billalabeitia Enrique ,   On behalf of the Spanish Oncology Genitourinary Group (SOGUG)
Published: May 2019

5040 Background: TMPRSS2-ERG fusion gene is a common driver of prostate cancer. The PREMIERE study is a phase II, single arm open-label, multicentre, clinical trial designed to analyse the predictive/prognostic value of TMPRSS2-ERG in first-line chemo-naïve mCRPC patients treated with enzalutamide. Methods: We centrally evaluated TMPRSS2-ERG in diagnostic samples using PCR, FISH and IHC for ERG. Among exploratory biomarkers we included plasma DNA, AR copy number by ddPCR and CTC by AdnaTest. PCWG2 criteria were used for outcome evaluation. We correlated TMPRSS2-ERGand other exploratory biomarkers with mCRPC outcomes. Results: Ninety eight patients with median age 77 y (range 59-95), ECOG 0/1 (54/46%) with mts located in bone (82%), LN (48%) and visceral (17%). With a median FU of 37.3 months, PSA response was PSA50: 82% and PSA90: 53%; median PSA-PFS was 13.7m (95%CI 10.2-19.0), Rad-PFS 26.7m (95%CI: 22.0-NA) and OS 37.5m (95%IC: 33.7-NA). TMPRSS2-ERG was detected in 32 pts (33%), AR gain in 11 pts and CTCs in 35 pts. No differences were observed based on TMPRSS2-ERG status for PSA response (PSA50: 81% vs 83%; p=0.8), PSA-PFS (median 12.8 vs 14.7m; HR 0.98; 95%CI 0.58-1.67; p=0.95), Rad-PFS (median 28.4 vs 26.4m; HR 1.02; 95% 0.53-1.96, p=0.95) or OS (median 36.9 vs 38.1m; HR 1.23; 95%CI 0.69-2.21, p=0.48). Plasma AR gain was associated with worse PSA-PFS (median 4.2 vs 14.7 m; p<0.0001), Rad-PFS (median 3.6 vs 28.4m; p<0.0001) and OS (median 12.7 vs 38.1m; p<0.0001). Plasma DNA and CTCs were also associated with worse outcome. Multivariate analyses of exploratory biomarkers are included in the table. Conclusions: The fusion gene TMPRSS2-ERG is not predictive nor prognostic on enzalutamide treatment in first-line chemo-naïve mCRPC patients. Plasma AR gain and CTCs are strong independent biomarkers associated with adverse outcome. Multivariate analysis of exploratory biomarkers. Clinical trial information: NCT02288936. [Table: see text]
Integrating evolutionary dynamics into treatment of metastatic castrate-resistant prostate cancer (mCRPC): Updated analysis of the adaptive abiraterone (abi) study (NCT02415621).
Authors: Zhang Jingsong , Fishman Mayer N. , Brown Joel , Gatenby Robert A 
Published: May 2019

5041 Background: To achieve better prostate cancer control and to delay the emergency of treatment resistance, we developed an evolutionary game theory model using Lotka-Volterra equations with three competing prostate cancer "species": T+, Tp, and T-. T+ prostate cancer cells depend on exogenous androgen; Tp cells express CYP17A1, produce and depend on androgen; and T- cells are androgen-independent and abi-resistant. We applied this model to guide the on and off treatment cycles with abi for mCRPC. At the first interim analysis with 11 patients, this approach was shown to prolong the time to cancer progression with less than 50% drug usage compared to the conventional continuous Abi ( Nat Commun. 2017). Here we present the updated data of this phase 2 study. Methods: Men with asymptomatic or minimal symptomatic mCRPC were enrolled after they achieved > 50% PSA reduction with abi as a frontline therapy for mCRPC. The primary objective is feasibility and is measured by the percentage of abi responsive men who remain to be responsive to abi (defined as > 50% decline of the pre Abi PSA) after completing 2 adaptive treatment cycles. The secondary objective is to assess the clinical benefits by comparing the radiographic progression free survival (rPFS) in men undergoing adaptive Abi therapy to the historical AA 302 trial. Results: At the data cut off in Jan 2019, the study has completed enrollment for the non-African American cohort. 15 enrolled men had > 11 months of follow up. All 15 men were off Abi for at least 3 months before abi was restarted for PSA progression at cycle 1. Seven out of the 15 men had completed at least 2 adaptive therapy cycles. Four of the rest 8 men remained on study and have not reached cycle 2. Six men were off study due to radiographic progression at month 11, 20.4, 30, 30.5, 38 and 53 from their first dose of Abi. Compare to the 16.2 months median rPFS in the AA 302 trial, the median rPFS of the 15 men would be no less than 30 months (p = 0.0068, Fisher’s exact test). Their average usage of Abi was 49% of the continuous Abi. Conclusions: Adaptive Abi therapy is feasible in men who responded to Abi as a frontline therapy for mCRPC. The updated data are consistent with our initial finding that our adaptive therapy approach can prolong the time to cancer progression with less than 50% drug usage compared to the conventional continuous Abi. Clinical trial information: NCT02415621.
Impact of enzalutamide and sequential flutamide and enzalutamide therapy for castration-resistant prostate cancer after bicalutamide-combined androgen blockade therapy onoverall survival: A follow-up study of randomized phase 2 trial (OCCU-CRPC study).
Authors: Iguchi Taro , Tamada Satoshi , Kato Minoru , Yasuda Sayaka , Otoshi Taiyo , Machida Yuichi , Ohmachi Tetsuji , Ishii Keiichi , Iwata Hiroyuki , Yamamoto Shinji , Kanamaru Tomohiro , Morimoto Kazuya , Hase Taro , Tashiro Koichiro , Harimoto Koji , Deguchi Takashi , Adachi Takahisa , Iwamoto Katsuki , Takegaki Yoshinori , Nakatani Tatsuya ,   OCUU-CRPC Study Group
Published: May 2019

5042 Background: In Asia, bicalutamide-combined androgen blockade (CAB) is widely used to treat metastatic or locally advanced prostate cancer. Enzalutamide (ENZA) shows benefits in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC), although flutamide (FLU) is still used as an alternative anti-androgen therapy after bicalutamide-CAB. Methods: The multicenter open-label phase 2 trial OCUU-CRPC (NCT02346578) randomized patients (1:1) with CRPC after bicalutamide-CAB to ENZA (160 mg/day) or FLU (375 mg/day). Patients were stratified according to distant metastases. The primary endpoint was the prostate-specific antigen (PSA) response rate (≥50% decrease) at 3 months. The endpoints of this follow-up observational study include PSA progression-free survival of ENZA therapy (PSA-PFS-ENZA), time to treatment failure of ENZA therapy (TTF-ENZA), and overall survival (OS). Results: In total, 103 patients were randomized to ENZA (n = 52) and FLU (n = 51). Overall, 67% had distant metastases and 10% had prior radical therapy. Twenty-five (48%) and 38 (75%) patients, respectively, discontinued their assigned treatment because of progressive disease or adverse events (AEs) and were treated by standard of care. Of the 38 patients that discontinued FLU, 34 (89%) received ENZA as subsequent therapy. The median follow-up time was 14 months (ENZA, interquartile range (IQR): 9.5-24.8) and 17.2 months (FLU, IQR: 9.8-24.9). PSA-PFS-ENZA was longer in patients not treated with FLU (hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.14 to 0.63; p < 0.001), but there was no significant difference in TTF-ENZA (HR, 1.27; 95% CI, 0.73 to 2.19; p = 0.397)and OS (HR, 0.77; 95% CI, 0.31 to 1.89; p = 0.567) between the two groups. The AEs of ENZA were consistent with those observed in prior phase 3 trials. Conclusions: ENZA after bicalutamide-CAB resulted in greater PSA-PFS than sequential FLU and ENZA therapy. No differences were observed in TTF-ENZA and OS between ENZA after bicalutamide-CAB and sequential FLU and ENZA therapy. Clinical trial information: NCT02346578. [Table: see text]
Suppression of testosterone production using abiraterone acetate (AA) with or without androgen deprivation therapy (ADT) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Jha Gautam Gopalji , Jeff Engle 
Published: May 2019

5049 Background: Patients with metastatic prostate cancer (mPC) are treated with lifelong ADT even after progression and every treatment for mPC has been tested only in the setting of androgen deprivation. Androgen synthesis inhibitor AA which inhibits synthesis of androgen that later get converted to testosterone has been studied and approved only alongside ADT similar to all other agents that have no or limited activity on testosterone suppression. We reviewed the ability of AA to sufficiently suppress testosterone levels as compared to AA plus ADT and its potential impact on cost savings. Methods: This retrospective study included consecutive patients with mCRPC treated with AA alone or in combination with ADT (in absence of orchiectomy) who had been followed with serial testosterone values on therapy. A cost analysis was performed to determine the cost avoidance by omitting leuprolide injections while on AA. The cost avoidance was calculated by multiplying the total number of injections by the wholesale acquisition cost of $5252.86 for a three month leuprolide injection. Results: Of 57 patients included in the final analysis, 36 received AA plus ADT, 10 received AA alone, and 11 started off with AA plus ADT before transitioning to AA alone. Testosterone levels were drawn 235 times. Testosterone was undetectable (below < 2 ng/dl) in both arms, 134 of 152 in combination arm and 86 of 99 in the AA alone arm. The median testosterone concentration when detectable was 3 ng/dL in AA alone and 3.5 ng/dL in AA plus ADT. None in the combination arm and only one testosterone value in AA arm had testosterone > than 30 ng/dl. The mean duration of AA use in this study was close to one year, and the total duration of therapy was approximately 61 years which could result in elimination of 244 leuprolide administrations and approximately $1.29 million in total cost savings. Conclusions: AA alone is able to effectively suppress testosterone synthesis in patients with prostate cancer. ADT with GnRH agonist or antagonist can be safely withheld while on therapy with AA and testosterone values followed to confirm adequate androgen suppression. This has acquired new significance after studies in patients with hormone sensitive disease where median duration of treatment was 33 months which could translate to an avoidable expense of $55.5 million for 960 patients in ‘STAMPEDE’ study and $34.5 million in ‘LATITUDE’ study from leuprolide administration in combination arm.
Aggressive variant prostate cancer (AVPC) molecular signature in castration-sensitive, de novo metastatic prostate cancer (M1PCa).
Authors: Aparicio Ana , Zhang Miao , Ramesh Naveen , Wang Xuemei , Corn Paul Gettys , Zurita Amado J. , Davis John W. , Pettaway Curtis Alvin , Adibi Mehrad , Mcguire Sean Eric , Tu Shi-Ming , Wang Jennifer , Subudhi Sumit Kumar , Elsheshtawi Mohamed A , Efstathiou Eleni , Logothetis Christopher , Navin Nicholas , Troncoso Patricia , Chapin Brian Francis 
Published: May 2019

5052 Background: AVPC are a subset of prostate cancers (PC) that share clinical features with the small-cell prostate carcinomas, a rare morphological variant with atypical and virulent behavior. They are estimated to represent 30% of lethal PC and are characterized by a molecular signature of combined defects (≥2) in Tp53, RB1 and PTEN (AVPC_MS). The AVPC_MS is associated with androgen indifference in preclinical models and predicts for benefit from the addition of carboplatin to cabazitaxel in men with castration resistant prostate cancer (CRPC). The prevalence and significance of the AVPC_MS in castration sensitive M1PC is unknown. Methods: In a Phase II trial 119 men with M1PC treated with 6 months of standard systemic therapy (SST) were randomized to the addition of local therapy. PCa samples obtained at diagnosis and after 6 months of SST were stained for markers including Tp53, RB1 and PTEN, and subject to whole genome sequencing. Tp53 was considered defective if expressed in ≥ 10% of tumor cells, and RB1 and PTEN if in ≤ 10%. Progression free survival (PFS) was estimated from SST start. Results: To date specimens from 38 men have been evaluated. Immunohistochemistry (IHC) results are shown below. The median PFS of men with AVPC_MSPOSITIVE vs AVPC_MSNEGATIVEbaseline prostate tumors was 9.3 vs 15 months (HR 1.09, 95%CI 0.42-2.87, P=0.852). Conclusions: The rate at which the AVPC molecular signature is detected in castration sensitive M1PCa appears similar to that in CRPC. This may have therapeutic implications. Updated molecular and outcome data will be presented upon acceptance. [Table: see text]
Treatment sequence in elderly metastatic castration-resistant prostate cancer (mCRPC) patients (pts) in a prospective cohort study.
Authors: Mendez-Vidal Maria Jose , Lozano Rebeca , Castro Elena , Romero-Laorden Nuria , Rodriguez-Vida Alejo , Lainez Nuria , Hernandez Amaia , Villatoro Rosa , Zambrana Francisco , Guzman Jose Carlos Villa , García Domínguez Rocío , Galvan Ruiz Saray , Escribano Ricardo , Gallardo Díaz Enrique , Querol Rosa , Luque Raquel , Gonzalez del Alba Aránzazu , Puente Javier , Olmos David , Lorente David 
Published: May 2019

5053 Background: Abiraterone (Abi), enzalutamide (Enza) and docetaxel (Doc) are all valid first-line (1L) mCRPC treatment options. SIOG guidelines (Droz, Eur Urol 2017) recommend that fit elderly pts should receive the same treatment as younger patients. Evidence of the optimal treatment sequence in this patient subpopulation is lacking. Methods: We evaluated the outcome of elderly (≥ 75 years [yrs]) pts treated in the prospective PROREPAIR-B cohort study (NCT03075735). We assessed the impact of 1L treatment option (Doc vs Abi/Enza) on overall survival (OS) and progression-free survival (PFS) to 1L-therapy following PCWG2criteria. Uni- (UV) and multivariable (MV) cox-regression models were used. MV model covariates included local therapy, Gleason Score, stage IV at diagnosis, visceral metastases, ALP (≥ULN), LDH (≥ULN), haemoglobin (Hb; ≤LNL), albumin (≤LNL) and ECOG PS. Results: 419 pts were included in the study. Of these, 137 (32,7%) had age ≥ 75 yrs. 48 (35%) received docetaxel and 88 (64.2%) had Abi/Enza as first-line therapy. Of the 121 pts that progressed on 1L-therapy, 30 (24.8%) did not receive 2L therapy. Choice of 2L-therapy was: Doc in 37 (30,6%), Abi/Enza in 38 (31.4%), Cabazitaxel in 9 (7.4%) and Radium-223 in 7 (5.8%) pts. Pts treated with 1L-Doc had higher rates of visceral metastases (22.9% vs 5.7%; p=0.003), high ALP (68.8% vs 43.2%; p=0.004) and low Hb (12.5% vs 3.4%). PFS to 1L-therapy was longer for Abi/Enza than for Doc treated pts (9.6 vs 8.3m; HR: 0.52; p=0.001). The pattern of disease progression (PSA, radiographic, clinical) was similar in Doce and Abi/Enza treated pts. No difference between pts treated with initial Abi/Enza vs Doc was observed in OS (28.2 vs 24.8m; HR:1.18; p=0.474). No significant OS differences were observed in the MV model. Conclusions: No differences in OS were observed between treatment sequences starting with Doc vs Abi/Enza in pts ≥ 75 yrs. Pts treated with 1L-Doc had worse baseline prognostic features. Age should not be considered as a factor for treatment choice in elderly mCRPC pts based on treatment outcome.
Risk of depression following prostate cancer work-up: A nationwide study.
Authors: Friberg Anne Sofie , Brasso Klaus , Andersen Elisabeth Wreford , Larsen Signe Benzon , Helgstrand John Thomas , Røder Martin Andreas , Johansen Christoffer , Dalton Susanne Oksbjerg 
Published: May 2019

5061 Background: Little is known about the psychological impact of undergoing evaluation for prostate cancer (PCa). We investigated the risk of developing a depression following PCa work-up with benign and malignant findings, respectively, compared with cancer-free men. Methods: A nationwide cohort of men who underwent prostate needle biopsies in Denmark from 1997–2011 was identified through the Danish Prostate Cancer Registry. Primary outcome was indication of moderate to severe depression defined as hospital contact for depression or first redemption of a prescribed antidepressant. For comparison, we selected a minimum of five age-matched cancer-free men per man who had undergone PCa specific diagnostic work-up. We excluded men with other cancer, major psychiatric disorder or use of antidepressants up to three years before study entry. Information on outcome and covariates (age, period, cohabitation status, income quintile and comorbidity) were retrieved from National Danish registries. We illustrated the risk of depression by cumulative incidence functions. Data were analyzed using Cox models adjusted for possible confounders. Results: We identified 54,766 men who underwent work-up including transrectal biopsies of the prostate, among these, 21,419 biopsy sets were benign and 33,347 men were diagnosed with PCa. We found an increasing cumulative incidence of depression in all groups. However, men diagnosed with PCa had a significantly higher risk throughout up to 18 years of follow-up. The adjusted hazard ratio (HR) of depression in men diagnosed with PCa was increased throughout follow-up with the highest risk in the two years following diagnosis (HR 2.77, 95% CI 2.66–2.87). After undergoing biopsies, men with benign results had an increased risk of depression (HR 1.22, 95% CI 1.14–1.31) in the first two years compared with cancer-free men; hereafter, we found no difference. Conclusions: We found an increased risk of depression in men following diagnostic work-up for PCa compared with a matched background population. In men diagnosed with PCa, the risk remained increased throughout the study period. Future studies are needed to further analyze the impact of stage and treatment modalities.