bluuebunny/crossref_metadata_2025 huggingface dataset:
Independent validation of missense polymorphism in HSD3B1 in Japanese men treated with primary androgen-deprivation therapy for metastatic prostate cancer.
Authors: Shiota Masaki , Fujimoto Naohiro , Imada Kenjiro , Kashiwagi Eiji , Takeuchi Ario , Inokuchi Junichi , Tatsugami Katsunori , Kajioka Shunichi , Uchiumi Takeshi , Eto Masatoshi
Published: February 2018

179

Background: Recently, genetic polymorphism in HSD3B1 has been shown to be associated with oncological outcome when treated with androgen-deprivation therapy (ADT) for prostate cancer. However, its impact on prognosis among different ethnicities remains unclear. Then, we aimed to investigate the significance of missense polymorphism in HSD3B1 gene encoding 3β-hydroxysteroid dehydrogenase among men treated with primary ADT for metastatic prostate cancer. Methods: This study included 104 Japanese patients with metastatic prostate cancer treated with primary ADT. The association of HSD3B1 (rs1047303, 1245C) with clinicopathological parameters and prognosis, including progression-free survival and overall survival, was examined. Results: Clinicopathological parameters were comparable between men with homozygous wild-type and men with heterozygous and homozygous variant types in HSD3B1 gene. Men carrying heterozygous and homozygous variant types in HSD3B1 gene showed higher progression risk [hazard ratio (95% confidence interval), 2.34 (1.08–4.49), P = 0.033], but not any-caused death risk [hazard ratio (95% confidence interval), 1.36 (0.52–2.92), P = 0.50], compared with men carrying homozygous wild-type. Conclusions: This study confirmed the finding that HSD3B1 genetic variation is associated with high risk of progression in Japanese men treated with primary ADT for metastatic prostate cancer, suggesting universal significance among different ethnicities.
Luminal and basal subtyping of metastatic castration-resistant prostate cancer (mCRPC) and its clinical implications.
Authors: Kim Won , Small Eric Jay , Aggarwal Rahul Raj , Den Robert Benjamin , Lehrer Jonathan , Zhang Li , Youngren Jack , Goldstein Theodore C , Alumkal Joshi J. , Gleave Martin , Rettig Matthew , Evans Christopher P. , Beer Tomasz M. , Reiter Robert Evan , Huang Jiaoti , Thomas George V. , Davicioni Elai , Ryan Charles J. , Spratt Daniel Eidelberg , Feng Felix Y
Published: February 2018

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Background: The PAM50 gene expression classifier (PAM50) identifies luminal and basal subtypes and predicts response to androgen deprivation therapy in localized prostate cancer. The clinical utility of using PAM50 to molecularly subtype mCRPC was evaluated. Methods: PAM50 was applied to RNA expression data from 86 metastatic tumor biopsies from the SU2C-AACR-PCF West Coast Prostate Cancer Dream Team (WCDT; NCT02432001). Overall survival (OS) differences between luminal A (LuA), luminal B (LuB), or basal patients (pts) were determined using Kaplan-Meier analyses. PAM50 was also applied to 15,136 prospectively collected radical prostatectomy (RP) samples from the Decipher GRiD database (NCT02609269). Drug response signatures (DRS) for 89 drugs were derived using publicly available data from the NCI60 cell line panel, and applied to gene expression data from the RP samples to predict patient-specific drug sensitivities. Differences in DRS as a function of PAM50 subtype were assessed using the Pearson’s chi-squared test. Results: The application of PAM50 to mCRPC transcriptional data segregated pts into LuA, LuB, and basal populations (43%, 14%, and 43%, respectively). The median OS for LuA, LuB, and basal pts was 20.6 months, 9.5 months, and 10.4 months, respectively (p=0.04), which was consistent with localized prostate cancer where LuB pts have the worst prognosis. DRS analyses revealed statistically significant differences in drug sensitivities, with LuA and LuB pts predicted to be markedly more sensitive to docetaxel than basal pts (p<0.00001), and basal pts predicted to be markedly more sensitive to platinums and etoposide than LuA and LuB pts (p<0.00001). Conclusions: PAM50 subtyping is prognostic in mCRPC, with LuA pts demonstrating the longest OS. Luminal and basal subtypes have distinct in silico drug response profiles that may be associated with response to mCRPC therapies. Prospective testing of DRS as a biomarker to guide treatment in mCRPC is warranted. Clinical trial information: NCT02432001, NCT02609269.
Genomic variations associated with prostate cancer in large cohort of African American men.
Authors: Walter Rayford , Jordan Jennifer , Takhar Mandeep , Alshalalfa Mohammed , Dai Darlene , Erho Nicholas , Greenberger Mark , Bradley Randy , Davicioni Elai
Published: February 2018

20

Background: Racial disparities in prostate cancer (PCa) incidence and mortality are well known. PCa is known to be more aggressive in African American men (AAM) in terms of higher incidence and mortality rates. Here we validate a tumor gene expression pan-cancer race model in men with PCa and further characterize genomic differences that may contribute to disparate clinical outcomes Methods: We obtained de-identified genome-wide expression profiles from clinical use of the Decipher RP test in 9,953 men from the GRID registry database. A subset of men (n = 313) had known race status. A pan-cancer race model, developed to predict patient AAM race from analysis of gene expression patterns in 4,162 tumors from retrospective cohorts with known race status was applied to the prospective cohort for race prediction. Gene expression data was used to define genomic differences. Results: The race model has an AUC of 0.98 discriminating EAM from AAM in independent PCa cohort. The model was then applied to the 9,640 GRID patients with unknown race status and classified 6,831 as EAM, 1,058 as AAM with 1,751 as having indeterminate race. Characterizing the molecular subtypes, we found known and predicted AAM to be enriched with SPINK1+ tumors (21% and 24%, respectively) compared to predicted EAM (8%). In contrast, while ERG+ was found 22% and 19% in known and predicted AAM, respectively compared to 46% in predicted EAM. Based on PAM50 prostate cancer classifier, 61% of AAM were classified as basal-like tumors, whereas 41% were basal-like in EAM. Similarly, 28% of AAM had low AR-A while only 11% of EAM had low AR-A. AAM tumors had higher levels of immune infiltration signatures as well as higher scores for inflammatory and interferon gamma responses, and Interleukin 6 (IL6) signaling activity scores. AAM had lower DNA repair and glycolysis pathway activity compared to EAM Conclusions: Known and predicted AAM, were enriched with SPINK1+ tumors, higher immune infiltration and activation but lower ERG+, DNA repair and AR activity tumors. Using such large GRID data with known race, we will further understand the underlying causes associated with prostate cancer racial disparities which could lead to personalized diagnosis and treatment.
Medical resource utilization (MRU) of abiraterone acetate plus prednisone (AAP) added to androgen deprivation therapy (ADT) in metastatic castration-naive prostate cancer: Results from LATITUDE.
Authors: Li Tracy , Franco-Villalobos Conrado , Proskorovsky Irina , Sorensen Sonja V , Tran Namphuong , Sulur Giri , Chi Kim N.
Published: February 2018

201

Background: AAP + ADT demonstrated significant improvements in overall survival and disease progression in the LATITUDE trial. The objective of this analysis was to assess event-driven MRU from AAP + ADT vs ADT alone. Methods: MRU data from the LATITUDE trial were obtained and consisted of medical utilization other than that mandated by protocol while patients were on treatment. MRU types included overnight hospitalizations and length of stay (LOS), emergency room (ER) visits, radiotherapy, surgery, imaging, and specialist and general practitioner (GP) visits. Rates by treatment (per 100 person-years) and rate ratios were estimated using zero-inflated Poisson regression. Difference in average LOS between treatment arms was assessed using repeated measures regression. Results: A total of 1199 patients were evaluated. Statistically significantly lower rates (24% reduction) of hospitalizations were observed with AAP + ADT compared with ADT alone (Table). The most common hospitalization reasons were bladder/urethral symptoms and infections, lung infections, and musculoskeletal/connective tissue pain. Average LOS per hospitalization episode was similar. Statistically significantly lower rates of imaging (40% reduction) and radiotherapy were also observed for AAP + ADT vs ADT alone. Rates for specialist visits, surgery ER visits, and GP visits were not statistically different. Conclusions: Adding AAP to ADT does not increase MRU and leads to lower rates of hospitalization, imaging, and radiotherapy. This likely reflects the more favorable clinical outcomes with AAP + ADT therapy. Clinical trial information: NCT01715285. [Table: see text]
Changes in prostate cancer circulating tumor cell (CTC) numeration and gamma H2AX positivity before and after treatment with radium 223 for metastatic castrate resistant prostate cancer.
Authors: Zhang Jingsong , Mocha Jesse , El-Haddad Ghassan
Published: February 2018

211

Background: As an alpha-particle emitting radiopharmaceutical, R is indicated for symptomatic mCRPC patients with bone predominant metastases and no visceral metastases. The current R administration dose was calculated based on body weight and decay factor. This may not be an ideal dose to individual patient (pt) with different body mass and different burdens of bone metastases. We hypothesize that changes in CTC # and the DNA damage marker, γH2AX, could serve as readout for on target effects of R and conducted a pilot prospective biomarker study. Methods: Pts who received R as standard of care for mCRPC and had a baseline CTC # of ≥ 2 were eligible. CTC samples were collected prior to and between 24 and 96 hours post dose 1, 3 and 6 of R. CTC # and γH2AX positivity were performed by Janssen Diagnostics Lab. Results: 10 pts were enrolled and all had > 15 bone metastases at enrollment. 7/10 pts had prior Taxane-based chemotherapy. The median CTC # and γH2AX positivity prior to R were 21 (range: 3-250), and 33% (range: 3% to 80%) respectively. 8 pts completed all 6 doses of R; 2 pts completed 2 doses then elected to hospice due to rapid clinical decline. Among pts completed R, 4 (50%) had bone scan progression within 1 month. No decline in ALKP, PSA, CTC # or increase in gamma H2AX positivity were seen during treatment with R in these 4 pts. 2 pts had CTC # conversion to 0 after dose 3 R at week 9. Both pts had ALKP decline, but no PSA decline during treatment. 1 of these 2 pts had 100% positivity for gamma H2AX after dose 6 R and had prolonged post R PSA response with stable bone scans at last follow up 24 months after the first dose of R. Increases in CTCs’ γH2AX positivity, and > 50% decline of ALKP were observed in 2 pts with germline deleterious mutations in BRCA2 and PALB2. Both pts, however, had a rapid surge in CTC # and PSA after dose 3. Despite stable bone scans, both proceeded with chemotherapy within 2 months after completing dose 6 R. Conclusions: Increase in CTC # and no increase in γH2AX positivity were associated with lack of response to R. The lack of increase in the DNA damage marker, γH2AX, in pts without declines in ALKP, PSA, and CTC # suggests their R doses may need to be increased. Clinical trial information: NCT02981797.
Clinical outcome of patients with germline DNA repair mutations: Results from a retrospective international study.
Authors: Mateo Joaquin , Cheng Heather H. , Beltran Himisha , Dolling David , Xu Wen , Pritchard Colin , Mossop Helen , Rescigno Pasquale , Perez-Lopez Raquel , Sailer Verena , Kolinsky Michael Paul , Balasopoulou Ada , Bertan Claudia , Carreira Suzanne , Thorne Heather , Montgomery Robert B. , Sandhu Shahneen Kaur , Rubin Mark A. , Nelson Peter , De Bono Johann S.
Published: February 2018

218

Background: CRPC is enriched for germline mutations in DNA damage repair genes (gDDRm). BRCA2 mutations (g BRCA2m) associate with poor prognosis from localized PC, but prognostic and predictive value for standard therapy in CRPC is unclear. We reviewed clinical outcome of 390 patients previously tested for gDDRm. Methods: Patient records were reviewed for 372 patients from 3 institutions (Royal Marsden UK, Weill-Cornell NY, University of Washington, WA) with gDDRm status previously published (Pritchard et al, NEJM 2016) and 18 g BRCA1/2m carriers from KConFab consortium (Australia). Baseline characteristics and survival were annotated. Response (PSA50%/RECIST) and PFS (RECIST/PSA progression or start of a new therapy due to clinical progression) were collected for Abiraterone, Enzalutamide and Docetaxel. To account for potential differences between cohorts, a mixed effect model (Weibull distribution) with random intercept per cohort was pursued. Results: dDDRm status was available for n = 390 (60 gDDRm+, including 37 g BRCA2m, and 330 gDDRm-). Overall, 74% and 69% received Docetaxel and Abiraterone/Enzalutamide respectively; 47% gDDRm+ and 34% gDDRm- received PARPi and/or platinum. Median overall survival from CRPC was 3.0 vs 3.2 years in gDDRm+ vs gDDRm- (p = 0.73; g BRCA2m = 3.0 years, p = 0.72). Age and Gleason score at diagnosis were associated with survival from castration-resistance in multivariate analysis. Median PFS on Docetaxel for gDDRm+ (6.8 months; 6.3 for g BRCA2m) and gDDRm- (5.1 months) were not significantly different (p = 0.2). Similarly, RR to Docetaxel was similar for the two groups (61% vs 54% in gDDRm+ vs gDDRm-; 63% g BRCA2m). Median PFS and RR on first Abiraterone/Enzalutamide were similar across groups (PFS: 8.3 months gDDRm+, 8.3 months for gDDRm-; p = 0.9; RR 46% vs 56% respectively) The Interaction of PARPi/platinum therapy among gDDRm+ patients resulted in an aHR for OS from CRPC of 0.59 (95%CI 0.28-1.25; p = 0.17). Conclusions: In this retrospective analysis, CRPC patients with gDDRm still benefited from standard therapies similarly to non-mutation carriers; interpretation of survival data should consider the high proportion treated with PARPi/platinum.
Effect of germline DNA repair gene mutations on outcomes in men with metastatic castration-resistant prostate cancer receiving first-line abiraterone and enzalutamide.
Authors: Antonarakis Emmanuel S. , Lu Changxue , Luber Brandon , Wang Hao , Chen Yan , Silberstein John , Piana Danilo , Lai Zhao , Chen Yidong , Isaacs William B. , Luo Jun
Published: February 2018

221

Background: Inherited DNA repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood. Here we investigated the clinical significance of germline DNA repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line novel hormonal therapy (NHT), with a particular emphasis on BRCA1/2 and ATM mutations. Methods: We interrogated 50 DNA repair genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT: abiraterone or enzalutamide. We assessed the impact of germline DNA repair gene mutation status on ≥50% and ≥90% PSA response rates, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses. Results: Among 172 mCRPC patients, germline mutations (in any DNA repair gene) were found in 12.8% (22/172) of men, and germline BRCA/ATM mutations were found in 5.2% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs. no mutations) with respect to ≥90% PSA responses (78% vs. 28%, P = 0.004), PSA-PFS (HR 0.47, P = 0.061), PFS (HR 0.50, P = 0.090) and OS (HR 0.28, P = 0.059). In propensity score-weighted multivariable analyses, outcomes remained superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95%CI 0.25–0.92, P = 0.027), PFS (HR 0.52, 95%CI 0.28–0.98, P = 0.044) and OS (HR 0.34, 95%CI 0.12–0.99, P = 0.048), but this was not true for men with non- BRCA/ATM germline mutations (all endpoints, P > 0.10). Conclusions: Outcomes to first line NHT appeared better in mCRPC patients harboring germline BRCA/ATM mutations (vs. no mutations), but not for patients with other non- BRCA/ATM germline mutations. These results support the hypothesis that AR may promote DNA repair, and that inhibiting AR in the context of homologous recombination deficiency may lead to synthetic lethality.
Patterns of progression in bone and soft tissue following treatment with Ra-223 in metastatic castrate resistant prostate cancer (mCRPC).
Authors: McNamara Megan Ann , Ritz Michala , Chin Bennett , Oldan Jorge , Anand Aseem , Oyekunle Taofik , Anand Monika , Armstrong Andrew J. , George Daniel J.
Published: February 2018

222

Background: Bone scans were not obtained in the phase 3 ALSYMPCA trial, and retrospective series have reported varying rates of development of new lesions and resolution of existing lesions, following treatment with Radium-223 (Ra-223). Methods: We performed a retrospective chart review of all men with mCRPC who received at least one dose of Ra-223 at Duke Cancer Institute from June 1, 2013 to June 1, 2015, in order to specifically describe radiographic changes on bone scan and CT during and following treatment. Radionuclide bone scans were reviewed by two radiologists prior to, during, and following Ra-223 treatment. The automated bone scan index (aBSI) was generated at each time point using EXINI boneBSI v. 2. Results: We identified 61 men with mCRPC (72% white, 28% black, median age 70) who received ≥ 1 dose of Ra-223 (median 5 doses, range 1-6). Prior treatments included: abiraterone (71%), enzalutamide (71%), sipuleucel-T (59%), docetaxel (56%), and cabazitaxel (18%). At baseline, 46% of men had nodal metastases, 3% had liver metastases, and 3% had lung metastases. Post-treatment bone scans demonstrated 0, 1-4, 5-9, 10-20, and > 20 new bone lesions in 15%, 10%, 8%, 8%, and 18%, respectively; 10% had resolution of 1-4 bone lesions. Median aBSI was 2.56 at baseline and 3.07 post-treatment. Progression in soft tissue included lymph node (31%), liver (23%), lung (5%), and epidural (8%). Of men with available imaging during treatment, 10 of 14 (71%) had new lesions on bone scan, 15 of 27 (56%) progressed on CT, and 3 of 14 (21%) progressed on both bone scan and CT; these proportions were 44%, 16%, and 24% following treatment, respectively. Men with prior chemotherapy (n = 33) had higher rates of progression on CT during (73%) and after treatment (40%), compared to men with no prior chemotherapy (36% and 25%, respectively). Conclusions: In a heavily treated population of men with mCRPC, radiographic progression in bone and/or soft tissue is common during and shortly after completion of Ra-223 treatment. Patients with prior chemotherapy have higher rates of non-bone progression, compared to patients with no prior chemotherapy. Bone scan and CT imaging are recommended during and after Ra-223.
First interim results of the Radium-223 (Ra-223) reassure observational study in metastatic castration-resistant prostate cancer (mCRPC): Safety and baseline (BL) characteristics of U.S. patients (Pts) by prior/concomitant treatment (Tx).
Authors: Harshman Lauren Christine , Sartor A. Oliver , Richardson Timothy , Sylvester John , Song Daniel Y. , Mantz Constantine , Brookland Robert K. , Perlmutter Mark , Given Robert , Kalinovsky Jan , Babajanyan Svetlana , De Sanctis Yoriko , Higano Celestia S.
Published: February 2018

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Background: Ra-223, a targeted alpha therapy, extended survival and had a favorable safety profile at 3 years’ follow up in pts with mCRPC in the pivotal phase 3 ALSYMPCA trial. The maturing global, prospective, single-arm, observational REASSURE study, designed to evaluate long-term safety at 7 years’ follow up, enrolled pts with mCRPC with bone metastases planned to receive Ra-223. Methods: We performed a descriptive analysis of safety and BL characteristics of US pts according to prior or concomitant abiraterone/enzalutamide (abi/enza) or prior docetaxel/cabazitaxel (chemo) using data from the first planned interim analysis (pts receiving ≥1 Ra-223 dose; median follow up 8 mo). Results: 244 US pts were included; 80% had no prior chemo. Prior abi/enza and/or chemo pts had higher median BL PSA and were less likely to complete 5-6 doses (Table). Subgroups had similar median ALP, LDH and Hb. Overall, drug-related tx-emergent AEs occurred in 71 pts (29%) and serious AEs in 9 (3.7%). Most common AEs were diarrhea, fatigue and anemia. AE incidence was numerically higher in pts who received prior chemo and/or abi/enza. Clinical trial information: NCT02141438. Conclusions: To date, REASSURE has not revealed any new safety findings and most pts complete 5-6 Ra-223 doses in routine US clinical practice. Pts with prior tx lines had lower Ra-223 tx completion and higher AE incidence, likely reflecting greater disease burden, as evidenced by higher median BL PSA.[Table: see text]
Immunological and genomic correlates of response to anti-PD1 checkpoint therapy in mismatch proficient and deficient patients with metastasized castration resistant prostate cancer.
Authors: Smits Minke , van der Doelen Maarten Johannes , Westdorp Harm , van Oort Inge M. , Sedelaar Michiel , Van Der Heijden Antoine , Witjes Alfred , Schalken Jack A. , De Vries Jolanda , Gerritsen Winald R. , Gulley James L. , Mehra Niven
Published: February 2018

248

Background: Response to anti-PD1/PDL1 checkpoint therapy has been witnessed in only a minority of patients with castration-resistant prostate cancer (CRPC). Microsatellite instability (MSI) is the only biomarker predictive of response; additional immune and genomic correlates are needed to improve the proportion of patients that may benefit from checkpoint immunotherapy. Methods: CRPC patients were treated with anti-PD1 checkpoint immunotherapy in two basket-studies, depending on PDL1-positivity ( > 1%) or presence of MSI, and consented to prospective immune-oncology biomarker study. Genomic and immune correlates of response were studied in both MSI as microsatellite stable CRPC patients, and included PDL1 expression , whole genome sequencing on a baseline fresh metastatic biopsy, tumor microenvironment (immuno)profiling using multi-color immunohistochemistry, computational prediction of neoantigens, T-cell receptor sequencing and MHC-tetramer staining. Response was evaluated according to PCWG3 criteria and treatment was continued until radiological progression with lack of clinical benefit or toxicity. Results: At present 11 CRPC patients were included in the program and treated with nivolumab (n = 4) and pembrolizumab (n = 7). Treatment is currently ongoing in 7/11 (64%) of patients, with treatment discontinuation due to immune-related colitis (n = 2) and disease progression (n = 2). Biochemical PSA ( > 50%) responses were seen in both MSI and PDL1 positive patients. Median progression-free survival has not yet been reached. Translational studies on genomic and immune correlates of response will be presented in detail. Conclusions: Encouraging responses to anti-PD1 checkpoint immunotherapy were seen in CRPC patients selected for PDL1-positivity and MSI. An integrative biomarker suite will likely be needed to predict response to anti-PD1 therapy in CRPC.
Pembrolizumab for recurrent or advanced prostate cancer.
Authors: Higa Juliana , Wilenius Kirk , Weidhaas Joanne B. , Larsen Claire , Lam Richard Y. , Turner Jeffrey , Scholz Mark C.
Published: February 2018

250

Background: Two previous Phase II trials studying pembrolizumab (Pembro) in 38 patients suggest it may be efficacious for prostate cancer (PC). Methods: Fifty-four consecutive men with recurrent or advanced prostate cancer were treated with 1 to 9 cycles of Pembro 200 mg every 3 weeks with or without SBRT at a private medical oncology clinic specializing in PC. Charts were retrospectively reviewed for response and toxicity. Definitions: Response (R) = >50% PSA decline; Progressive Disease (PD) = >50 % PSA increase. Stable Disease (SD)= neither response or progression. Results: 43 men completed 3 cycles of Pembro and were evaluable for toxicity. Toxicity was comparable to reports with other cancers besides PC, with 30.2% (13/43) having Grade 2 or higher toxicity. 31 men completed 4 cycles of Pembro and were evaluable for response. For the 31, the median Gleason score was 4+4=8. Treatment prior to Pembro was enzalutamide (26), abiraterone (18), and sipuleucel-t (23) and docetaxel (20). All but 4 men were castrate resistant (CRPC). Ten men got SBRT to a metastasis shortly before or during Pembro. Number of mutations were determined by the Guardant 360 assay. 17/31 (55%) were responders (19%) or had stable disease (35%). Characteristics of the two subgroups, R (6/31) + SD (11/31) versus PD (14/31), are presented in the table. Conclusions: Disease stabilization or response occurred in slightly more than half of the men treated with 4 or more cycles of Pembro. These positive responses were more common in men with lower PSA, fewer bone mets, fewer mutations, less previous chemotherapy, and there was a trend toward greater benefit in castrate sensitive disease and older men. In a separate abstract related to this patient cohort, the predictive ability of inherited mutations disrupting microRNA signaling were assessed for their capacity to predict toxicity (n=40). The table shows medians of the subgroups in the left 5 columns and the total number of patients in the right 3 columns for the 31 patients evaluable for response. [Table: see text]
Cotargeting AR signaling and cell cycle: A randomized phase II study of androgen deprivation therapy with or without palbociclib in RB-positive metastatic hormone sensitive prostate cancer (mHSPC).
Authors: Palmbos Phillip Lee , Tomlins Scott A. , Agarwal Neeraj , Twardowski Przemyslaw , Morgans Alicia K. , Kelly William Kevin , Arora Vivek , Antonarakis Emmanuel S. , Siddiqui Javed , Daignault Stephanie , Knudsen Karen E. , Feng Felix Y , Hussain Maha
Published: February 2018

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Background: Palbociclib, a CDK4/6 inhibitor, blocked proliferation and promoted G1 arrest in an Rb and Cyclin D dependent manner in preclinical models of HSPC. Alterations in this pathway contribute to the development of CRPC. We hypothesized that co-targeting AR (ADT) and cell cycle (palbociclib) would improve outcomes including PSA RR at 28 weeks in mHSPC pts. Methods: mHSPC pts with Rb intact tumors based on IHC of metastatic biopsy were stratified and randomized (1:2) to Arm A: ADT or Arm B: ADT+ palbociclib (125mg 3 weeks on, 1 week off). Primary endpoint is confirmed PSA RR (≤ 4 ng/mL) after 28 weeks of therapy. With 20 patients randomized to ADT and 40 to ADT + palbociclib there is a 64.2% power to detect a 20% difference in proportions with a one-sided type I error of 0.10 using the mid p-value method of the Fisher’s exact test. Secondary endpoints include safety/tolerability, biochemical and clinical PFS, PSA and radiographic RR and exploratory biomarkers (circulating DNA, tumor cells and transcriptome). Results: 72 eligible pts (median age 67, PSA 73ng/mL) with newly diagnosed mHSPC were registered and underwent biopsy (41 soft tissue, 31 bone). 64/72 (90%) had adequate tissue for RB assessment and 62/64 (97%) retained RB expression (IHC). 62 pts were stratified by disease extent and early initiation of ADT, and randomized. 60 pts initiated therapy (Arm A: 20; Arm B: 40). Neutropenia was the most common G3/4 AE (Arm A: 0% Arm B: 33%). 80% of pts (Arm A: 16/20, Arm B: 32/40; p = 0.87) on both arms met primary PSA endpoint (≤4ng/mL at 28 weeks). PSA undetectable rate at 28 weeks was Arm A: 50% (10/20) and Arm B: 43% (17/40; p = 0.5). Measurable disease RR: Arm A: 78% and Arm B: 74%. 12-month biochemical PFS was Arm A 69% (95%CI: 43-85%), Arm B 74% (95%CI: 56-85%). Clinical PFS is not mature and correlative biomarker studies are ongoing. Conclusions: Co-targeting of AR signaling and cell cycle in a tissue biomarker preselected trial is feasible in mHSPC. RB loss was rare in this population. PSA RR at 28 weeks was not impacted by addition of palbociclib to ADT. Important clinical PFS data will be reported when mature. Clinical trial information: NCT02059213.
Cell-free DNA (cfDNA) analysis and evaluation of BRAF amplifications and mutations in metastatic castration-resistant prostate cancer.
Authors: Steinwald Peter , Ledet Elisa , Christensen Bryce Raymon , Moses Marcus Marie , Chapman Lynne , Shahbandi Ashkan , Cotogno Patrick , Schiff Joshua , Layton Jodi Lyn , Lewis Brian E. , Sartor A. Oliver
Published: February 2018

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Background: Cell-free DNA (cfDNA) is an accessible method for characterizing tumoral alterations. We report cfDNA screenings of prostate cancer pts positive for BRAF amplifications/mutations in pts with metastatic CRPC. Methods: Guardant360 testing (Guardant Health, Inc.) assesses cell-free DNA analysis using sequencing to identify genomic alterations in 73 cancer-related genes in circulation. A total of 133 metastatic castrate resistant prostate cancer (mCRPC) pts in various stages of therapy had Guardant cfDNA analyses. Treatment histories prior to testing and concurrent cfDNA alterations were analyzed. Results: BRAF amplifications were detected in 32 (24%) mCRPC pts; 5 pts had concurrent BRAF mutations. Of the mutations detected, only one (K601E, n = 2) was a known activating mutation while all others were variants of unknown significance (VUS). One K601E mutation pt had no other cfDNA alterations. Additionally, 4 pts without BRAF amplification had VUS BRAF mutations. BRAF amplification pts had ≥ 2 concurrent gene amplifications/alterations with the median being 8. The most common recurrent amplifications/alterations were AR (75%), p53 (59%), CDK6 (53%), MET (50%), and MYC (50%). Abiraterone (Abi) and/or Enzalutamide (Enza) resistance was associated with BRAF amplification (p = 0.0042). Non-Abi/Enza resistance pts were less likely to have BRAF amplification. The 2 pts with BRAF K601E mutation were treated with targeted protocol therapy without success however one K601E pts was subsequently treated with cabazitaxel+carboplatin which produced a positive clinical response and a 99.79% reduction in PSA. Conclusions: Pts resistant to Abi/Enza have an increased risk of developing BRAF amplifications. BRAF amplifications arise in the context of multiple additional detectable cfDNA alterations. Identification of actionable mutations, such as BRAF K601E, illustrates the potential for cfDNA testing to direct pt treatment. As cfDNA profiling continues to expand, the ability translate alterations into clinically actionable strategies is critical.
Minority Equity and Recruitment Into Trials program: Self-assessment of disease-specific cancer clinical trial recruitment patterns at a comprehensive cancer center.
Authors: Borno Hala , McGuire Joseph P. , Griffin Ann C. , Ryan Charles J. , Kaplan Celia , Small Eric Jay
Published: February 2018

267

Background: Prostate cancer disparities research has largely focused on access to care, treatment, and outcomes. Disparities based on race/ethnicity in clinical trial (CT) participation are less well understood. African American men are known to have an increased risk of developing and dying from prostate cancer compared to their white counterparts yet remain underrepresented in prostate cancer CTs. The goal of this study was to examine the demographic accrual patterns in prostate cancer CTs at an academic cancer center. Methods: A retrospective analysis of demographic data of cancer cases per year was performed from: 1) the central cancer registry of California, Surveillance, Epidemiology, and End Results; 2) new patients (“analytic cases”) identified in the University of California, San Francisco (UCSF) cancer registry; and (3) the UCSF Clinical Trials Management System database. The Catchment Area for the center was prospectively defined, and patients from this region comprised 98% of all cancer cases seen at UCSF. Descriptive statistics were applied to characterize CT accruals for men with prostate cancer relative to cases in our Catchment Area. Results: Overall there were 67,046 new cancer cases of all types in the Catchment Area, of which 6,558 were prostate cancer cases. The distribution of patients with prostate cancer by ethnicity/minority status are summarized (Table). Conclusions: The distribution of minority accruals to prostate cancer CTs conducted at academic cancer centers may not reflect overall accruals to all CTs. At UCSF, the accrual of Latino men with prostate cancer to CTs was representative of the Catchment Area, whereas Asian and Black men were under-represented. These results suggest that tailored, disease-specific interventions are required to achieve equitable CT recruitment.[Table: see text]
CaPSURE update: Examining primary treatment and survival among men with prostate cancer and bony metastatic disease.
Authors: Borno Hala , Cowan Janet E. , Zhao Shoujun , Carroll Peter , Ryan Charles J.
Published: February 2018

275

Background: New data is emerging to guide primary treatment of patients with metastatic (M+) disease. Among the CHAARTED and LATITUDE cohorts, 27.2% and 5% of patients with M+ disease had prior local therapy, respectively. This study utilizes the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry to examine survival among patients with M+ disease. Methods: CaPSURE is a registry of men diagnosed with prostate cancer. We examined sociodemographics, disease biology, primary therapy, and survival among patients who were diagnosed with cM+ disease or developed metastasis. We performed a multivariate Cox model to evaluate the association between timing of metastasis and prostate cancer specific mortality (PCSM), adjusted for age, primary treatment, and follow-up therapy. Results: Of the 14,753 patients diagnosed with prostate cancer from 1990-2016, 717(4.9%) had M+ disease. 328(2.2%) had cM+ disease and 389(2.6%) progressed to bony metastasis. For all patients with M+ disease, 490(68.3%) were > = 65 yo, 627(87.4%) had Medicare, and 239(33.3%) had an annual income < $30,000 (P < 0.01). PSA at diagnosis was > 20 ng/mL for 355(49.5%) and biopsy Gleason was 4+3 or 8 to 10 for 403(56.2%) (P < 0.01). Among patients with cM+ disease, 49(14.9%) received primary local therapy and 279(85.1%) received primary hormonal therapy. Among patients who progressed to M+ disease, 258(66.3%) received primary local therapy and 131(33.7%) received primary hormonal therapy. The risk of PCSM was worse for patients with M+ disease who received hormonal therapy for primary treatment compared to patients who received combined local and hormonal therapy (HR 1.47 (95% CI 1.15 to 1.88), P < .01). Timing of metastatic disease was not associated with PCSM. Primary treatment with hormonal therapy compared to local therapy was associated with higher risk of PCSM (HR 1.40 (95% CI 1.00-1.97), P = 0.05) for patients diagnosed with Gleason > = 4+3 disease. Conclusions: In our analysis, patients with primary local therapy were examined as a subset of all patients with M+ disease. We observed that patients with cM+ disease have a worse prognosis then patients who develop M+ disease with antecedent primary local therapy.
Statin use and outcomes of patients (pts) with metastatic castration resistant prostate cancer (mCRPC) being treated with abiraterone (Abi).
Authors: Gordon Jacob A , Eigl Bernhard J. , Locke Jennifer A. , Pond Gregory Russell , Chehroudi Cyrus , Khalaf Daniel , Chi Kim N. , Cox Michael E.
Published: February 2018

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Background: Epidemiologic studies support an association between statin use and improved prostate cancer specific mortality. Several different biologic mechanisms for such an effect have been proposed, including a potential role in reducing androgen precursor bioavailability. It is hypothesized that statins may therefore improve outcomes specifically in patients treated with the CYP17 inhibitor Abi. Di Lorenzo (2017) recently published an analysis of 187 pts showing a relationship between Abi and improved survival (OS). We report the results of a larger confirmatory analysis in a separate cohort. Methods: Disease outcome and statin use were assessed retrospectively in locally advanced or metastatic CRPC patients receiving Abi in British Columbia, Canada. The Kaplan-Meier method was used to estimate survival times, Cox proportional hazards and logistic regression were used to investigate factors potentially prognostic of overall survival and PSA response respectively. A multivariable model was constructed using factors with limited missing data and known biologic rationale. Impact of statins was then assessed adjusting for factors included in the multivariable model. Results: 301 patients receiving Abi were assessed, of whom 84 (28%) were statin users. Median OS of Abi patients was 11.3 months for non-statin users and 16.2 months for statin users (hazard ratio = 0.79, 95% CI = 0.61-1.03, p = 0.079). Effect of statin use remained borderline after adjusting (n = 279, hazard ratio = 0.78, 95% CI = 0.59-1.04, p = 0.087) for age, prior prostatectomy, radiation, Docetaxel, time from diagnosis, neutrophils-lymphocyte ratio and presence of metastases. Forty-eight percent of statin users and 37% of non-statin users had a PSA response (multivariable odds ratio = 1.59, 95% CI = 0.91-2.78, p = 0.11). Conclusions: Although limited by sample size, our data showed a trend that statins may mildly enhance the anti-tumor effects of Abi in CRPC patients. These results support the findings of Di Lorenzo et al. (2017), and suggest that depletion of de novo cholesterol production may further limit androgen synthesis in concert with CYP17A1 inhibition. Further studies are warranted.
Incidences of visceral metastases from prostate cancer increase after progression of castration-resistant status.
Authors: Iwamoto Hiroaki , Izumi Kouji , Kadono Yoshifumi , Mizokami Atsushi
Published: February 2018

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Background: Recent advances in castration-resistant prostate cancer (CRPC) therapy are remarkable, but we often experience a case of visceral metastases caused after CRPC progression and few data regarding the onset of visceral metastases after CRPC are available. In the present study, we retrospectively examined visceral metastases of prostate cancer (PCa) at our hospital. Methods: Between 2000 and 2014, 1038 patients with PCa were treated at our hospital. We collected and retroactively analyzed data from medical charts. Variables of interest included the ratio to cause CRPC and visceral metastases, the relationship between the number of therapeutic agents and visceral metastases, overall survival (OS), etc. Results: Patients were diagnosed with T1-2 (72.1%), T3-4 (24.5%), N1 (10.3%), M1 (11.7%), and M1c (1.8 %). There were 144 (19.8 %) patients with CRPC and 43 (33.1%) patients with visceral metastases after CRPC progression. Patients with CRPC showed significantly longer OS than patients without CRPC (p < 0.01). Of those with CRPC, patients with visceral metastases exhibited significantly shorter OS (p < 0.01). Patients with liver/adrenal gland metastases exhibited the shortest OS of all patients with CRPC (p = 0.02). At diagnosis, the sites of visceral metastases included lung (89.5%), liver (5.3%), and adrenal glands (5.3%). After CRPC progression, new visceral metastases were found in the lung (47.3%), liver (43.6%), and adrenal gland (9.1%). Liver and adrenal gland metastases significantly increased after CRPC progression (p < 0.01). Additionally, the rate of new visceral metastases significantly increased as the number of therapeutic agents increased (p < 0.0001). The median number of therapeutic agents being used was determined at the onset of visceral metastases to the lung (1), liver , and adrenal grand (5) (p < 0.001). Conclusions: Our findings confirmed that visceral metastases, especially liver and adrenal gland metastases, confer the worst survival. These metastases significantly increased as patients underwent powerful androgen deprivation therapy . Future prognostic improvements are expected through continued development of therapies for visceral metastases.
NanoVelcro CTC purification systems for expressional analysis of circulating tumor cells from prostate cancer patients.
Authors: Jan Yu Jen , Chen Jie-Fu , You Sungyong , Yao Nu , Cheng Shirley , Freeman Michael , Tseng Hsian-Rong , Posadas Edwin M.
Published: February 2018

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Background: Circulating tumor cells (CTCs) are blood borne tumor cells shed from all present disease sites, including primary and metastatic tumors. Researchers have been exploring the use of CTCs to identify important transcriptomic features such as androgen receptor splicing variants in prostate cancer (PCa). Newer transcriptomic profiles such as the prostate cancer classification system (PCS) have been developed that may be useful clinically. Over the past decade, we have been developing the NanoVelcro CTC purification system which includes different stimuli-responsive strategies to capture and release viable CTCs with high efficiency and preserve intact RNA. The purified CTCs can then be subjected to transcriptomic analysis such as qPCR, ddPCR and NanoString’s nCounter system. In this study, we benchmarked the efficiency of these platforms for purification of CTCs from blood specimens and the feasibility for detection of PCa-related RNA signatures from purified CTCs. Methods: NanoVelcro CTC purification system is combined with qPCR and ddPCR platform to detect PCa-specific RNA targets in purified CTCs from patients' blood samples. We also developed a modified PCS panel of 30 genes adapted to the nCounter platform and tested purified CTCs from PCa patient blood samples and performed differential expression analysis for PCa disease profiling. Results: PCa-related RNA signals were detected in 16/17 CTC(+) PCa patients, including 3 of 4 non-metastatic patients. We also tested the gene expressions of the modified PCS panel using 48 patient blood samples. Upon performing clustering of samples based on the RNA signatures, we found the differential expression of CTC-target genes grouped patients in a manner which strongly related to drug response and clinical status. Conclusions: We have shown the capability of purifying CTCs with high efficiency using our system, while retaining cell viability and molecular integrity, allowing for detection of PCa-specific RNA signatures from CTCs. Our non-invasive, blood-based assay will be useful for detecting and continuous monitoring molecular alterations related to disease evolvement, addressing an unmet need for PCa clinical care.
PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC).
Authors: Hussain Maha , Fizazi Karim , Saad Fred , Rathenborg Per , Shore Neal D. , Demirhan Eren , Modelska Katharina , Phung De , Krivoshik Andrew , Sternberg Cora N.
Published: February 2018

3

Background: Men with M0 CRPC and rapidly rising prostate-specific antigen (PSA) are at high risk of developing metastatic (M1) CRPC. ENZA improves overall survival (OS) and radiographic progression-free survival in men with M1 CRPC. We hypothesized that ENZA will improve metastasis-free survival (MFS) in men with M0 CRPC. Methods: Eligible men with M0 CRPC, PSA doubling time ≤ 10 mo and PSA ≥ 2 ng/mL at screening continued androgen deprivation therapy (ADT) and were randomized 2:1 to ENZA 160 mg or PBO. The primary endpoint was MFS. Secondary endpoints included time to PSA progression, time to first use of new antineoplastic therapy, OS and safety. Results: In 1401 men, ENZA significantly prolonged median MFS (36.6 mo vs 14.7 mo [ P < .0001]), time to first use of new antineoplastic therapy (39.6 mo vs 17.7 mo [ P < .0001]) and time to PSA progression (37.2 mo vs 3.9 mo [ P < .0001]) compared to PBO (Table). In the first interim analysis of OS there was a trend in favor of ENZA (hazard ratio [HR] = 0.80; P = .1519). Median duration of treatment was 18.4 mo vs 11.1 mo for ENZA vs PBO. Adverse events (AEs) were higher with ENZA vs PBO (any grade: 87% vs 77%; grade ≥ 3: 31% vs 23%; serious: 24% vs 18%); 10% with ENZA discontinued treatment due to AE vs 8% with PBO. Conclusions: In men with M0 CRPC and rapidly rising PSA, ENZA treatment resulted in a clinically meaningful and statistically significant 71% reduction in the risk of developing M1 CRPC. AEs were consistent with the established safety profile of ENZA. Clinical trial information: NCT02003924. [Table: see text]
Adverse effect of docetaxel versus surveillance after radical prostatectomy for high risk prostate cancer: Post-hoc analysis of the prospective randomized, open-label phase III SPCG 12 trial.
Authors: Ahlgren Goran M. , Borre Michael , Sengelov Lisa , Tammela Teuvo L. J. , Kellokumpu-Lehtinen Pirkko , Sverrisdottir Asgerdur , Iversen Jon Reidar ,   Scandinavian Prostate Cancer GROUP
Published: February 2018

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Background: Adjuvant chemotherapy is standard treatment for other solid tumours, but so far has not proven effective in prostate cancer. Methods: Open-label, randomised multinational phase III trial. Enrolment 459 patients after prostatectomy. Inclusion criteria high risk (pT2 margin positive or pT3a Gleason score (GS) ≥4+3, pT3b or lymph node positive disease ≥GS 3+4). Patients assigned (1:1) to either six cycles of adjuvant docetaxel 75mg/m2 every three weeks without daily prednisone (ArmA) or surveillance (Arm B) until endpoint was reached. Primary endpoint was PSA progression ≥0.5ng/ml. Results: Median time to progression, death or last follow up was 56.8 months. Primary endpoint was reached in 190/459 patients (41.4%), 103 of 230 (44.8%) patients in Arm A and 87 (38.0%) of 229 in Arm B. In Kaplan-Myer analysis, there was evidence of non-proportional hazards over time. When 76 patients with PSA > 0.2 after surgery were excluded from the analysis, the outcome showed proportional hazards and favoured surveillance in the KM-analysis (p = 0.02). The significant favour of surveillance remained in a Cox multivariate analysis including Gleason score, pT-stage, surgical margins and lymph node status (p = 0.03). Limitations were that not all patients received docetaxel by protocol, some patients received radiation treatment before end-point and lack of stratification for PSA after surgery. Conclusions: Adjuvant docetaxel without hormonal therapy or continuous corticosteroids may have an adverse effect on biochemical progression in patients with low or undetectable levels of PSA after surgery. Clinical trial information: NCT00376792.