bluuebunny/crossref_metadata_2025 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.
SLFN11 expression (exp) in castration-resistant prostate cancer (CRPC) patients (pts) to predict response to platinum-based chemotherapy (PLT).
Authors: Conteduca Vincenza , Puca Loredana , Ku Sheng-Yu , Hess Judy , Kearney Megan , Fernandez Luisa , Bareja Rohan , Vlachostergios Panagiotis J. , Sigouros Michael , Mosquera Juan Miguel , Sboner Andrea , Nanus David M. , Elemento Olivier , Dittamore Ryan , Tagawa Scott T. , Beltran Himisha
Published: May 2019

5065

Background: Schlafen family member 11 (SLFN11) sensitizes tumor cells to DNA-damaging agents and has been investigated as a potential predictive biomarker of response to PLT and PARP inhibitors, especially in small cell lung cancer (Lok, CCR 2017; Pietanza, JCO 2018). We aimed to explore the predictive/prognostic role of SLFN11 in PLT-treated CRPC. Methods: We assessed tumor exp of SLFN11 in PLT-treated, metastatic CRPC pts by RNAseq (N=27) and/or CTCs (N=20) (via the Epic Sciences platform). In addition, tumor morphology for neuroendocrine (NE) features and genomic status of select genes (ie, AR, TP53, RB1, BRCA2, BRCA1, ATM) by whole exome sequencing were evaluated. Statistical comparisons used Cox regression analysis and Kaplan Meier method for the association with overall/radiographic progression free survival (OS/rPFS). A dose response curve with PLT was performed in patient-derived organoids using Cell Title Glo according to the manufacturer’s protocol. Results: 41 CRPC (including 20 CRPC-NE) treated with PLT monotherapy (N=3) or PLT combination therapy (N=38) between August 2013 and December 2017 were evaluated. Median age was 67.1 years (range 51-91). Median number of prior therapies was 2 (range 1-7). A longer median rPFS was observed in all SLFN11+ pts treated with PLT (regardless of histology, RB1, TP53, PTEN, or DNA repair status) compared to SLFN11- [5.2 vs 2.3 months, HR 3.5, 95%CI 1.6-7.7, P<0.0001]. No association was reported for OS. On multivariable analysis (Table), SLFN11 was an independent factor associated with rPFS. Organoids derived from patient tumors expressing SLFN11 showed sensitivity to PLT in vitro. Conclusions: SLFN11 exp identifies both CRPC and CRPC-NE pts with a better response to PLT. Patient-derived organoids expressing SLFN11 confirmed increased sensitivity to PLT. Larger prospective evaluation of therapy decisions based on SLFN11 exp is now required. [Table: see text]
Association of plasma DNA repair deficient (DRD) status with clinical outcome of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with abiraterone acetate (AA) plus prednisone/dexamethasone (+P/D).
Authors: Shen Dong , Thomas Shibu , Lefresne Florence , Gormley Michael , Urtishak Karen , Lahaye Marjolein , Tombal Bertrand F. , Merseburger Axel S , Parekh Trilok V. , Ricci Deborah S. , Attard Gerhardt
Published: May 2019

5066

Background: Somatic DRD deficiency in 15-30% of mCRPC pts have been observed and inhibition of enzyme poly ADP ribose polymerase (PARP) could prove beneficial. We aimed to define DRD status using plasma from pts treated on AA and evaluate associations with prospectively-collected outcome measures. Methods: Plasma DNA samples (128 baseline [BL], 134 cycle 2 day 1 [C2D1], 46 progression [PROG]) from chemotherapy-naïve mCRPC pts in a phase 2 study (NCT01867710) evaluating AA+P/D were subjected to custom target-capture next-generation sequencing. DRD assay was optimized and validated to detect pathogenic point mutations, small insertions/deletions, and copy number alternations (DRD+) in 8 DRD genes: BRCA1, BRCA2, FANCA, ATM, CHEK2, HDAC2, BRIP1, and PALB2. Analysis for genomic aberrations was a secondary exploratory objective. Associations with overall survival (OS), progression-free survival (PFS), and radiographic PFS (rPFS) were assessed using Cox regression models and Kaplan Meier analyses. Results: 11.7% of BL and 17.4% of PROG were DRD+. Bi-allelic was observed in 73.3% of BL DRD+ samples. Shorter PFS was observed in BL DRD+ vs DRD- (5.3 vs 15.5 mo; HR: 2.32; 95%CI:1.39-4.28; P < 0.002). Median PFS for BL DRD biallelic + vs DRD biallelic- was 5.1 vs 15.4 mo (HR: 2.49; 95% CI: 1.23-4.38; P < 0.0095). For multivariate analysis using DRD+, ALP, and LDH as covariates, DRD+ (HR: 2.1; 95% CI: 1.18-3.75; P < 0.012) and high ALP (HR: 1.66; 95% CI: 1.08-2.56; P < 0.021) were strongly associated with worse PFS. Median OS for BL DRD+ vs DRD- was 28.8 vs 41.3 mo (HR: 1.67; 95%CI:0.88-3.18; P = 0.116). Median rPFS for BL DRD+ vs DRD- was 16.2 vs 20.9 mo (HR: 1.64; 95%CI:0.83-3.21; P = 0.152). Of 39 Pts with BL, C2D1 and PROG samples, 3 were DRD+ (7.7%) at all 3 timepoints, 3 (7.7%) only at BL, 3 (7.7%) only at PROG (bi-allelic), 2 (5.1%) had extra deletion at PROG. Conclusions: Patients with mCRPC harboring DRD+ have worse outcomes with AA and represent a population with an unmet medical need.
Cell-free DNA as a biomarker for taxane treatment in advanced prostate cancer.
Authors: Sumanasuriya Semini , Seed George , Mehra Niven , Christova Rossitza , Pope Lorna , Goodall Jane , Flohr Penelope , Fowler Gemma , Bianchini Diletta , Rescigno Pasquale , Carreira Suzanne , Yuan Wei , Macé Sandrine , Chadjaa Mustapha , De Bono Johann S.
Published: May 2019

5070

Background: Antitumor efficacy of chemotherapeutic drugs docetaxel and cabazitaxel against hormone-sensitive and castration-resistant prostate cancer (CRPC) is well recognized. The identification and validation of minimally invasive biomarkers of taxane response remain of paramount importance. Methods: Serial pre-, during and post-treatment plasma samples were collected prospectively from two large Phase III clinical trials, FIRSTANA (NCT01308567) and PROSELICA (NCT01308580). Chemotherapy-naïve patients (pts) were treated with docetaxel (75 mg/m2) or cabazitaxel (20 or 25 mg/m2) in FIRSTANA, and pts previously treated with docetaxel received cabazitaxel (20 or 25 mg/m2) as second-line chemotherapy in PROSELICA. Plasma cell-free DNA (cfDNA) was extracted, low-pass whole genome sequencing (lp-WGS) libraries were prepared using the QIAGEN QiaSeq FX DNA library kit, and samples sequenced on the Illumina NovaSeq 6000. Targeted next-generation sequencing (NGS) on a custom-made AmpliSeq panel of 30 genes, pre-selected for putative roles in taxane resistance, was also performed. lp-WGS copy number (CN) profiles were generated using ichorCNA (v0.1.0) and targeted NGS variant calls derived using IonReporter software. Results: Overall, lp-WGS data was generated from 265 samples (99 pts; 51 treated on the FIRSTANA study, 48 treated on the PROSELICA study), acquired at three time-points (pre-, during and at progression). Average cfDNA input was 10 ng and mean coverage achieved was ~2X (SD 1.2X). We observed changes in lp-WGS tumor purity over time as a result of therapy; samples from non-responding pts exhibited significantly higher tumor purity values post-treatment compared with samples from responding pts (p = 0.02). Targeted NGS results were available from 294 pts (153 from FIRSTANA, 141 from PROSELICA), and changes in tumor purity were also associated with treatment response (p = 0.04). CN frequency of key CRPC genes was similar to previously reported datasets; several aberrant loci associated with response to taxane therapy. Conclusions: cfDNA lp-WGS may have clinical utility in the management of lethal prostate cancer. Funding: Sanofi. Clinical trial information: NCT01308580, NCT01308567.
Examination of the additive value of CTC biomarkers of heterogeneity (Het) and chromosomal instability to nuclear-localized (nl) AR-V7+ CTCs in prediction of poor outcomes to androgen receptor signaling inhibitor (ARSi) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Scher Howard I. , Schonhoft Joseph , Graf Ryon P , Jendrisak Adam , Barnett Ethan , Jayaram Anuradha , Winquist Eric , Landers Mark , Wang Yipeng , Allan Alison L , Attard Gerhardt , Dittamore Ryan
Published: May 2019

5075

Background: Prediction of ARSi benefit in mCRPC is an unmet medical need. Recently, the Epic Sciences CTC based nl AR-V7 test validated as a predictive biomarker in two multi-center validation studies and has received Medicare coverage for use in mCRPC. While the nl AR-V7 biomarker is highly specific to resistance and predictive of improved response with taxane Rx, it is a measure of just one mechanism of resistance to ARSis. CTC Het measured by the Shannon Index and CTC chromosomal instability measured by predicted number of Large Scale Transitions (pLST) have both been associated with poor OS to ARSis in previous analysis. Here we investigate the relationship of Het and pLST to nlAR-V7 in order to assess multi-clonal resistance and determine if these biomarkers can provide added sensitivity in the nlAR-V7 negative patient population. Methods: 275 blood samples from 2nd+ line mCRPC patients prior to treatment with ARSi (n=148) or taxanes (n=137) were obtained between 2012 and 2017 from 3 clinical centers. Detectable CTCs in each blood sample were assayed for nlAR-V7, Het, and pLST using the Epic Sciences platform. Biomarkers were analyzed in context of each other and outcomes including clinical co-variates. Results: 94% of samples had detectable CTCs, 84% were evaluable for Het analysis (> 2 CTCs), and 76% were evaluable for pLST (> 3 CTCs). Conclusions: Addition of CTC Het (Shannon Index) and CTC chromosomal instability (pLST) biomarkers to nlAR-V7 identifies an additional 15% of mCRPC pts (38% of total) that are predicted to have poor survival to AR signaling inhibitors. [Table: see text][Table: see text]
Clinical and safety outcomes of TALAPRO-2: A two-part phase III study of talazoparib (TALA) in combination with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Agarwal Neeraj , Shore Neal D. , Dunshee Curtis , Karsh Lawrence Ivan , Sullivan Beth , Di Santo Nicola , Elmeliegy Mohamed , Lin Xun , Czibere Akos Gabor , Fizazi Karim
Published: May 2019

5076

Background: TALA is a dual-mechanism PARP inhibitor that inhibits PARP catalytic activity and traps PARP on DNA. ENZA is a novel hormonal therapy approved to treat castration resistant prostate cancer. TALA + ENZA may improve clinical outcomes for men with mCRPC. However, TALA, is a substrate for efflux drug transporters P-gp and BCRP. Prior to the initiation of TALAPRO-2 part 1, the in vivo effect of ENZA on exposure of P-gp and BCRP substrates, such as TALA, had not been evaluated. Methods: TALAPRO-2 part 1 was designed to determine TALA starting dose based on safety and pharmacokinetics (PK) evaluation of TALA + ENZA. Pts were ≥18 yrs of age, had ECOG PS ≤1, with no prior systemic treatment for mCRPC. The starting dose of TALA in the first 13 pts was 1 mg once daily (QD) + ENZA 160 mg QD (1 mg QD cohort). Based on safety review of prespecified target safety events and PK data, TALA dose was reduced to 0.5 mg QD; additional pts were treated with a starting dose of TALA 0.5 mg QD + ENZA 160 mg QD (0.5 mg QD cohort). Results: 19 pts were enrolled in part 1 (1 mg QD cohort, 13; 0.5 mg QD cohort, 6). The median (range) age was 71 yrs (52-82). As of the analysis cutoff date, the median treatment duration was 25 and 11 wks for the 1 mg QD and 0.5 mg QD cohorts, respectively. Treatment-emergent adverse events (TEAEs) occurred in 19 pts. The most common TEAE, anemia, occurred in 76.9% and 33.3% of pts in the 1 mg QD and 0.5 mg QD cohorts, respectively. TEAEs that led to TALA dose reduction occurred in 6 pts (46.2%) and 0 pts in the 1 mg QD and 0.5 mg QD cohorts, respectively. In the 1 mg QD cohort, target safety events were reported for 7 pts (53.8%) vs 0 in the 0.5 mg QD cohort. 92% and 100% of pts had a 50% decline from baseline in PSA in the 1 mg QD and 0.5 mg cohorts, respectively, demonstrating preliminary anti-tumor activity. PK data showed that ENZA increased TALA exposure and that TALA 0.5 mg QD + ENZA maintained similar TALA exposure to that achieved with 1 mg QD monotherapy. Conclusions: TALA 0.5 mg QD + ENZA 160 mg QD had a manageable safety profile in pts with mCRPC and will be the starting dose for the randomized portion of TALAPRO-2. Clinical trial information: NCT03395197.
Evaluation of the patient-reported outcomes common terminology criteria for adverse events (PRO-CTCAE) with abiraterone acetate plus prednisone (AAP), degarelix (D), or the combination in men with biochemically recurrent prostate cancer (BCRPC).
Authors: Autio Karen A. , Antonarakis Emmanuel S. , Baser Raymond , Stein Mark N. , Shevrin Daniel H. , Vaishampayan Ulka N. , Mayer Tina M. , Morris Michael J. , Slovin Susan F. , Heath Elisabeth I. , Tagawa Scott T. , Rathkopf Dana E. , Milowsky Matthew I. , Harrison Michael Roger , Beer Tomasz M. , Balar Arjun Vasant , Armstrong Andrew J. , Paller Channing Judith , Basch Ethan M. , Scher Howard I.
Published: May 2019

5080

Background: Patient-reported symptoms using the PRO-CTCAE provide insights into the patient experience with care. Earlier use of AAP (an androgen biosynthesis inhibitor plus prednisone) with androgen deprivation therapy in castration sensitive disease may lead to increased symptoms. We previously reported a randomized phase 2 trial of intermittent AAP, D, or AAP+D in BCRPC (NCT01751451) and now share the PRO-CTCAE results. Methods: Men were randomized 1:1:1 to AAP, D, or AAP+D for 8 months, then entered follow up with PSA, testosterone, and safety monitoring. PRO-CTCAE was elicited from patients monthly for hot flashes (HF), fatigue, arthralgias, myalgias, anxiety, depression, sexual function, plus overall QOL. Changes from baseline to end of treatment were compared between groups. AUCs were calculated for each item as a measure of symptom severity over time. Results: 110 men were included. Compliance with PRO-CTCAE reporting from baseline to EOT was 93%. HF did not differ between AAP+D and D, but were increased relative to AAP (all p < 0.05). These differences were consistent when HF were measured as an AUC (all p < 0.01). Fatigue severity did not differ between groups however men receiving AAP reported a small worsening in activity interference from fatigue as compared to AAP+D (p < 0.05). Overall QOL scores were high and did not differ with AAP+D relative to AAP or D. Conclusions: Collection of PRO-CTCAE was feasible and did not demonstrate differences in fatigue, HF, or QOL between AAP+D and D. Comparisons of PRO-CTCAE to matched clinician-reported AEs, and changes in PRO-CTCAE with testosterone recovery during follow up are planned. Clinical trial information: NCT01751451.
Targeting backdoor androgen synthesis through AKR1C3 inhibition: A presurgical hormonal ablative trial in high risk localized prostate cancer (PC).
Authors: Graham Laura , Reder Nicholas , Gulati Roman , Grivas Petros , Wright Jonathan L. , Yu Evan Y. , Hou Wendy , Nega Katie , Yezefski Todd , Montgomery Robert B. , Mostaghel Elahe A. , Ellis William J. , True Lawrence D. , Lin Daniel W. , Nelson Peter , Schweizer Michael Thomas
Published: May 2019

5081

Background: Studies have shown that localized PCs may resist neoadjuvant androgen receptor (AR)-targeted therapies as a result of persistent intraprostatic androgens, likely arising through upregulation of steroidogenic enzymes. Therefore, we sought to evaluate clinical effects of combinatorial AR-targeted therapy, including indomethacin (Indo) to inhibit the steroidogenic enzyme AKR1C3, in men with high risk PC undergoing radical prostatectomy (RP). Methods: This was an open label, single-site, Phase II neoadjuvant trial in men with localized high to very-high risk PC, as defined by NCCN criteria. Patients received 12 weeks of neoadjuvant apalutamide (Apa), abiraterone (Abi) plus prednisone, degarelix, and Indo at their respective FDA-approved doses followed by RP. The primary objective was to determine the pathologic complete response (pCR) rate. Secondary objectives included assessing for minimal residual disease (MRD) (i.e. ≤0.25 cm3 tumor volume corrected for cellularity), measuring intraprostatic androgens and assessing molecular features associated with drug resistance. Twenty evaluable patients provided 91% power (one-sided alpha = 7.5%) to detect a difference in pCR rate of 5% (H0) vs. 25% (H1). Results: Twenty-two patients enrolled and 20 were evaluable for the primary endpoint (1 patient came off to pursue stereotactic radiosurgery; 1 was removed after developing grade 2 transaminitis). At baseline, the median PSA was 10.1 ng/mL (4.4-159.4), 4 (20%) patients had Gleason grade group (GG) 4 disease and 16 had GG 5 disease. At RP, 1 (5%) patient had a pCR, 6 (30%) had MRD, 18 (90%) had ypT3 disease and 7 (35%) had lymph node (LN) metastases. Treatment was generally well tolerated and adverse events were consistent with each individual drug’s known safety profile. Additional follow up data and correlative work will be presented at the meeting. Conclusions: In our cohort of men with high-risk PC, pCR rates remained low even with combinatorial AR-directed therapy. Ongoing pharmacodynamic studies aimed at determining if Indo effectively inhibited AKR1C3 will provide important insights regarding the utility of targeting this steroidogenic enzyme. Clinical trial information: NCT02849990.
Is there a role for testosterone replacement therapy in reducing biochemical recurrence following radical prostatectomy?
Authors: A T Edward , Huynh Linda My , Towe Maxwell M , See Kaelyn , El Khatib Farouk , Yafi Faysal A
Published: May 2019

5085

Background: Historically, the use of testosterone replacement therapy (TRT) has not been recommended in men with a history of prostate cancer (PC). However, low testosterone levels are significantly associated with metabolic complications, decreased sexual function, and (more recently) high-grade PC. In 2009, in hopes of improving sexual function outcomes in men following radical prostatectomy (RP), we began treating low-risk patients with TRT. The current study examines the impact of TRT on biochemical recurrence (BCR). Methods: Between December 2009 and June 2018, a cohort of 850 patients underwent RP by a single surgeon. 152 (18%) men were postoperatively placed on TRT for recovery of sexual function. All data was prospectively collected and retrospectively analyzed. TRT patients were proportionately matched to 419 control patients by pathologic Gleason Grade Group (GGG) and stage. Univariate and multivariate comparisons were used to compare rates and time to BCR (two consecutive PSAs ≥ 0.2 ng/dl); Cox regression modeling was used to generate a survival function at the mean of covariates. Results: There were no statistically significant differences in preoperative PSA, age, prostate weight, pathologic GGG and stage between the control versus TRT groups. Median follow-up time was 3 years in both groups. 7/152 (4.6%) and 39/419 (9.3%) patients experienced BCR in the TRT versus control groups, respectively (unadjusted, p=0.068). In adjusted time to-analysis, TRT was an independent predictor of recurrence-free survival, after controlling for GGG, p-stage, preoperative FT and PSA. A patient on TRT was approximately 53% less likely to experience a BCR (OR: 0.534, 95%CI: 0.288-0.993). Conclusions: After accounting for pathologic GGG, stage, and other significant covariates, the use of TRT independently reduced recurrence post-RP. These results suggest the need for a multi-center randomized control trial.
Patient-reported outcomes (PROs) from KATHERINE: A phase III study of adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab (H) in patients (pts) with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer.
Authors: Schneeweiss Andreas , Loibl Sibylle , Mamounas Eleftherios P. , Minckwitz Gunter von , Mano Max S. , Untch Michael , Huang Chiun-Sheng , Rastogi Priya , Conte Pier Franco , D'hondt Veronique , Redondo Andres , Stamatovic Ljiljana , Bonnefoi Herve R. , Castro Salguero Hugo Raul , Fischer Hans Holger , Wahl Tanya A. , Song Chunyan , Blotner Steven , Trask Peter , Geyer Charles E.
Published: May 2019

513

Background: The phase 3 KATHERINE (NCT01772472) study, met its primary endpoint by demonstrating significantly improved invasive disease-free survival with adjuvant T-DM1 compared to H in pts with residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy. PROs are reported here. Methods: Eligible pts had HER2-positive early breast cancer, received taxane- and H-containing neoadjuvant therapy (with/without anthracyclines) followed by surgery, and had residual invasive disease in the breast and/or axillary nodes. Pts were randomized to 14 cycles of adjuvant T-DM1 (3.6 mg/kg IV q3w) or H (6 mg/kg IV q3w) and adjuvant endocrine and radiation therapy per standard of care. The EORTC Quality of Life Questionnaire–Core 30 (QLQ-C30) and QLQ–Breast Cancer (QLQ-BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6 and 12 months’ follow-up. Results: Of 1,486 pts randomized (T-DM1, n = 743; H, n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 post-baseline PRO assessments. During the study, pts in both arms had similar mean scores on the QLQ-C30 and QLQ-BR23 function and symptom scales. There was no clinically meaningful change (≥10 points) from baseline in the mean scores in either arm, including on symptoms similar to AEs seen with T-DM1 (eg, fatigue). While more pts in the T-DM1 arm reported clinically meaningful deterioration in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 61%), nausea/vomiting (39% vs. 30%), and systemic therapy side effects (49% vs 36%) at ≥1 assessment, the proportion reporting clinically meaningful change in functioning was similar between arms at any given assessment. Conclusions: Mean scores showed only small deterioration from baseline in patient-reported treatment-related symptoms in both study arms. While more pts in the T-DM1 arm reported deterioration at some point in several symptoms, baseline global health status and functioning were generally maintained in both arms over the treatment course. Clinical trial information: NCT01772472.
Results of randomized phase II trial of neoadjuvant carboplatin plus docetaxel or carboplatin plus paclitaxel followed by AC in stage I-III triple-negative breast cancer (NCT02413320).
Authors: Sharma Priyanka , Kimler Bruce F. , O'Dea Anne , Nye Lauren Elizabeth , Wang Yen Y. , Yoder Rachel , Prochaska Lindsey Hastings , Wagner Jamie L. , Amin Amanda Leigh , Larson Kelsey , Balanoff Christa , Elia Manana , Crane Gregory James , Madhusudhana Sheshadri , Hoffmann Marc Steven , Sheehan Maureen , Rodriguez Robert R. , Jensen Roy A. , Godwin Andrew K. , Khan Qamar J.
Published: May 2019

516

Background:
Addition of neoadjuvant carboplatin (Cb) to paclitaxel (T) followed by doxorubicin + cyclophosphamide (AC) improves pathologic complete response (pCR) rate compared to T/AC in TNBC. An anthracycline-free regimen of Cb plus docetaxel (D) also yields high pCR rates in TNBC, and patients achieving pCR with this regimen demonstrate excellent 3-year outcomes without adjuvant anthracycline. This study was designed to compare the efficacy of neoadjuvant regimens CbT→AC and CbD in TNBC.
Methods:
In this multicenter study, eligible patients with stage I–III TNBC were randomized (1:1) to either paclitaxel 80 mg/m2 every week X 12 + carboplatin (AUC 6) every 3 weeks X 4, followed by doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 every 2 weeks X 4 (CbT→AC, Arm A), or to carboplatin (AUC 6) + docetaxel (75 mg/m2) every 21 days X 6 cycles (CbD, Arm B). The primary endpoint was pCR (no evidence of invasive tumor in the breast and axilla). The two regimens were compared for differences in pCR, residual cancer burden (RCB), treatment delivery, and toxicity.
Results:
Between 2015 and 2018, 100 patients were randomized; 48 to Arm A and 52 to Arm B. Median age was 52 years, median tumor size was 2.7 cm, 30% were lymph node-positive and 17% carried a
BRCA1/2
mutation. Baseline demographic and tumor characteristics were balanced between two arms. pCR was 55% (95%CI: 41%-59%) in Arm A and 52% (95%CI: 39%-65%) in Arm B, p
=
0.84. RCB 0+1 rate was 67% in both arms. Grade 3/4 adverse events were more common in Arm A compared to Arm B (73% vs 21%, p < 0.0001), with most notable differences in rates of G3/4 neutropenia (Arm A = 60%, Arm B = 8%, p = 0.0001), febrile neutropenia (Arm A = 18%, Arm B = 0%, p = 0.0001), and G3/4 anemia (Arm A = 46%, Arm B = 4%, p = 0.0001). 81% of Arm A patients completed all 4 doses of AC and 4 doses of Cb, and 71% completed > 9 doses of T. 90% of Arm B patients completed all 6 doses of CbD (p = 0.034).
Conclusions:
The non-anthracycline platinum regimen of CbD yields pCR and RCB 0+1 rates similar to 4-drug regimen of CbTàAC, but with a more favorable toxicity profile and higher treatment completion rate. The CbD regimen should be further explored as a way to de-escalate therapy in TNBC.
Clinical trial information: NCT02413320.