bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic validation of three-tiered sub-classification of high-risk prostate cancer.
Authors: Muralidhar Vinayak , Zhang Jingbin , Spratt Daniel Eidelberg , Feng Felix Y , Davicioni Elai , Yousefi Kasra , Wang Natalie , Choeurng Voleak , Nguyen Paul L.
Published: March 2019

17

Background: Recent data and National Comprehensive Cancer Network (NCCN) guidelines suggest that high-risk prostate cancer (cT3-4, Gleason score ≥ 8, or prostate-specific antigen [PSA] > 20 ng/mL) is a heterogenous group in terms of long-term patient outcomes. We sought to determine whether sub-classification of high-risk prostate cancer based on clinical factors correlates with genomic markers of risk. Methods: We identified 3,220 patients with NCCN unfavorable intermediate-risk (n=2,000) or high-risk (n=1,220) prostate cancer. We defined the following sub-classification of high-risk prostate cancer based on previously published data: favorable high-risk (cT1c, Gleason 6, and PSA > 20 ng/mL or cT1c, Gleason 4+4=8, PSA < 10 ng/mL); very high-risk (cT3b-T4 or primary Gleason pattern 5); and standard high-risk (all others with cT3a, Gleason score ≥ 8, or PSA > 20 ng/mL). We used a set of 37 previously published genomic classifiers, including the 22-gene Decipher assay, to determine whether high-risk genomic features correlated with the clinical sub-classification of high-risk prostate cancer. Results: Among those with favorable high-risk, standard high-risk, and very high-risk prostate cancer, 50.4%, 64.2%, 81.6% had a high-risk Decipher score, respectively (p < 0.001). Among 36 other genomic signatures, 33 had a similar increasing trend across the three sub-classes of high-risk (p < 0.05 after correction for multiple hypothesis testing). Patients in the three sub-classes of high-risk disease were positive for a median number of 5, 7, and 14 high-risk signatures. Under a novel clinical-genomic risk group classification (Spratt et al., 2017), 27.5%, 19.7%, and 7.0% of patients with favorable, standard, or very high-risk disease would be re-classified as intermediate-risk, respectively. In comparison, among those with unfavorable intermediate-risk prostate cancer, 38.2% had a high-risk Decipher score and would be re-classified as clinical-genomic high-risk. Conclusions: Genomic markers of risk correlate with the clinical sub-classification of high-risk prostate cancer into favorable high-risk, standard high-risk, and very high-risk disease, validating the prognostic utility of this stratification.
A phase I and randomized phase II study of cabozantinib plus docetaxel and prednisone (C+DP) versus docetaxel and prednisone (DP) alone in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Al Harthy Munjid , Madan Ravi Amrit , Karzai Fatima , Petrylak Daniel Peter , Kim Joseph W. , Arlen Philip M. , Theoret Marc Robert , Marte Jenn , Bilusic Marijo , Couvillon Anna , Chun Guinevere , Owens Helen , Hankin Amy , Cordes Lisa M. , Figg William Douglas , Gulley James L. , Dahut William L.
Published: March 2019

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Background: A phase I study of Cabozantinib (C) in combination with docetaxel (D) and prednisone (P) in patients (pts) with mCRPC determined that 40 mg daily was the maximum tolerated dose of C in combination with D and P (C+DP). We report a pooled analysis of the phase I and randomized phase II study comparing C+DP to DP alone. Methods: Eligible pts had mCRPC without prior chemotherapy in the castrate setting. All pts received a fixed dose of D (75 mg/m2IV day one of each 21 day cycle) and P (5 mg PO twice daily), and in the C+DP group, C at three escalating dose levels: 20 mg, 40 mg, or 60 mg in the phase I cohort (all PO daily) and 40 mg daily in the phase II cohort. Results: A total of 32 pts received C+DP (19 pts in phase I and 13 pts in the phase II cohort). 12 pts received DP alone. Baseline characteristics for C+DP vs DP included median age 69 (45 – 84) vs 69 (50-83) and median PSA 74.8 ng/ml (0.01-4093.7) vs 309.5 ng/ml (94.6 – 2649) respectively. Clinical trial information: NCT01683994. 18/32 C+DP pts had previous enzalutamide or abiraterone, with a median PFS of 13.6 months (95% CI: 5.2 – 21.0). 23/32 pts (72%) treated with C+DP required dose reduction or discontinuation of C, and 10/32 (31%) required C discontinuation. 2/32 patients (6%) in the C+DP group died on protocol, possibly related to study drug (sudden death NOS/venous thromboembolism). Grade 4 adverse events (AEs) in the C+DP group included: neutropenia (28%), leukopenia (6%), pulmonary embolism (3%), and mucositis (3%) and in DP: hyperglycemia (8%). Grade 3 AEs (>10%) in C+DP included: neutropenia (31%), febrile neutropenia (16%), leukopenia (13%), hypophosphatemia (13%) and in DP: anemia (17%). Conclusions: In pts with mCRPC, C+DP is associated with a greater PFS and PSA responses compared to DP alone. Toxicities with the combination were manageable. Further study is required to better define the potential benefits of C+DP in mCRPC.[Table: see text]
In geriatric evaluation, some iadl (Katz) scale items are more predictive of efficacy and toxicity than ADL (Lawton) scale or Charlson Comorbidity Index in metastasic castration-resistant protate cancer (mCRPC) patients treated with cabazitaxel in a weekly schedule.
Authors: Climent Duran Miguel Angel , Pérez-Valderrama Begoña , Mellado Begona , Fernandez Parra Eva , Fernandez Calvo Ovidio , Anido Herranz Urbano , Domenech Montserrat , Hernando Polo Susana , Arranz Jose Angel , Caballero Diaz Cristina , Juan Fita María José , Castellano Daniel E. , ochoa De Olza Maria
Published: March 2019

176

Background: Cabazitaxel (CBZ) improves overall survival in mCRPC that progresses during or after docetaxel treatment. CABASEM is a phase II study to evaluate the efficacy and safety of a weekly schedule of CBZ for 'unfit' (ECOG2, previous neutropenic fever with docetaxel, or radiotherapy to <25% of areas of bone marrow reserve) mCRPC patients after docetaxel failure. Fragility scales were performed to patients included before treatment and results are described. Methods: All 70 patients were treated with CBZ 10 mg/m2/wk 4 administration every 5 weeks. Geriatric fragility scales performed were Lawton daily day activities (ADL), BPI score, Katz instrumental daily day activities (IADL) and Charlson index. General and specific items have been analyzed in relation with toxicity and efficacy (clinical benefit (OR+SD), PSA response, composite PFS, PSA-PFS, and overall survival) in all patients and in older than 70 years. Results: Median age 73 (range 54-85). Charlson index and ADL scale had not relationship with any toxicity observed and any efficacy outcome in the whole group nor in older than 70. IADL independence grade was related to survival in the whole group (p=0,025) and older than 70 (p=0,02). In the whole group, some IADL items were associated with PSA response (buying, p=0.003; cooking, p=0.06; and IADL independence grade p=0.01), PSA PFS (telephone use, p=0.01; handle finances, p=0.06), composite PFS (telephone use, p=0.013; housekeeping, p=0.03; handle finances, p=0,06) and OS (telephone use p=0.001; laundry, p=0.008; handle finances, p=0.02 and IADL dependence grade, p=0.003). Only any grade diarrhea and grade 2 neutropenia was associate with buying (p=0.025) and cooking (p=0.05) IADL items respectively, in patients older than 70 years. Conclusions: IADL scale and items seem to be more related to efficacy (OS, PSA response, PFS, clinical benefit and PSA PFS) than ADL and Charlson scales in mCRPC older than 70 years treated with weekly cabazitaxel. No clear association of scales and items with toxicity were observed in this group of patients. Clinical trial information: NCT01518283.
Age-related variation in gene alteration frequency in metastatic prostate cancer.
Authors: Chalmers Zachary Rockow , Frampton Garrett Michael , Ross Jeffrey S. , Hussain Maha H. A. , Abdulkadir Sarki
Published: March 2019

178

Background: Despite advances in therapy, metastatic prostate cancer (mPCA) remains lethal. Younger men with mPCA have a significantly greater risk of mPCA-related death compared to men diagnosed later in life. This suggests that early-onset mPCA is a uniquely aggressive subtype of disease, however, the genomic drivers have not been explored. Here, we analyze data from 2,196 mPCA specimens profiled as part of routine clinical care. Methods: Comprehensive genomic profiling was performed by hybridization capture of exonic regions from either 236, 315 or 324 cancer-related genes and select introns from 19 genes commonly rearranged in cancer. Libraries were sequenced to high, uniform coverage and assessed for all classes of genomic alterations. Tumor mutational burden (TMB) was determined from 1.1 Mb of sequence and microsatellite instability (MSI) from 114 loci. Results: 336 (15.3%) men were < 60 years old (yo), and 1,860 (84.7%) were ≥60 yo at time of biopsy. Lymph node, liver, and bone were the three most common metastatic sites in both groups, accounting for 75% of all specimens. Patients < 60 yo harbored significantly fewer AR and PTEN point mutations when compared to patients ≥60 yo (OR = 0.48, p < 0.001; OR = 0.51, p = 0.01). Copy number alterations in PTEN and CDKN2A/B were significantly more common among young patients (OR = 1.46, p = 0.003; OR = 1.91, p = 0.04). AR copy number alterations were significantly less common among young patients (OR = 0.57, p < 0.001). Although uncommon in mPCA, markers of genomic instability including MSH2 mutations and MSI were both significantly less common among patients < 60 yo (0.00% vs. 1.29%, p = 0.04; 0.89% vs. 3.06%, p = 0.03). There were no significant differences in the frequency of TP53, APC, BRCA2, ATM, and CDK12 point mutations, MYC copy number alterations, or TMPRSS2-ERG fusions. The average TMB was not significantly different between young and old patients, with 3.26 and 5.79 mutations per Mb, respectively (p = 0.19). Conclusions: Younger men with mPCA appear to represent a genomically distinct disease subtype. To better define this population, we are prospectively investigating the genomic, genetic, and environmental risk factors through an ongoing PCF funded clinical trial.
Are prostate cancer patients with BRCA1 and BRCA2 mutations safe for active surveillance?
Authors: Dall'era Marc , Evans Christopher P. , Pan Chong-Xian , Parikh Mamta , Lara Primo , McPherson John
Published: March 2019

19

Background: Active surveillance (AS) is recommended as a treatment option for men presenting with low risk (Gleason 3+3) and some intermediate risk (Gleason 3+4) prostate cancer. BRCA1 or 2 germline mutations have been implicated in prostate cancer pathogenesis. It is unknown if germline BRCA1/2 mutations in AS candidacy are associated with more aggressive histologic grade, higher stage or other worse genetic alterations, such as RB1 and p53 deletions. Methods: We analyzed sequencing data from 498 men who underwent radical prostatectomy from The Cancer Genome Atlas (TCGA) data set. The primary outcome was the difference in the proportions of AS candidates among subjects with and without BRCA homodeletions. Tests for differences in the proportions were conducted using Fisher’s Exact Test. Equivalence tests for proportions of AS candidates were conducted using the two-one sided tests (TOST) method. As a secondary outcome we studied the associated coincident mutations in the men with BRCA1 and BRCA2 homodeletions. Results: Forty-one men (8%) of the cohort had homodeletion of BRCA1 or BRCA2. Ten men (2%) had complete loss of BRCA1 while 31 (6%) had loss of BRCA2. Rates of candidacy for AS based on histology and stage (defined as stage T2, Gleason 6) are not different between subjects with and without BRCA 1 or 2 homodeletions, within an equivalence margin of 10 percentage points. These findings are similar when the AS criteria are modified to add Gleason 3+4 subjects. Fifty percent of men with organ confined (pT2), 3+3 and 3+4 prostate cancer with BRCA1 or BRCA2 homodeletions had concomitant RB1 deletions compared with 16.5% of the entire cohort (p = 0.002). This was primarily driven by BRCA2 deletions co-occurrent with RB1 deletions (log OR: 2.4, p < 0.001). Twenty-nine percent of men from this group had concomitant p53 deletions compared to 7.5% of the entire cohort (p = 0.004). Conclusions: Men with prostate cancer and BRCA1 or BRCA2 homodeletions present with similar stage and grade tumors than men without these deletions. Despite having low or low intermediate grade histology, BRCA1 and BRCA2 deleted tumors are enriched with deletions in RB1 and TP53, both of which are associated with more aggressive phenotypes and treatment resistance.
Radium-223 treatment patterns in a large real-world population.
Authors: Zhao Hanson Hanqing , Howard Lauren , de Hoedt Amanda , Terris Martha K , Amling Christopher L. , Kane Christopher J. , Cooperberg Matthew R. , Aronson William J. , Polascik Thomas , Freedland Stephen J.
Published: March 2019

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Background: For men with symptomatic metastatic castration resistant prostate cancer (mCRPC), radium-223 was shown to improve overall survival in the phase III, double blind ALSYMPCA trial. Despite the observed benefits, the application and practice patterns of Radium-223 outside of clinical trials are largely unknown. Here we aim to better characterize the use of radium-223 in a large and heterogeneous real-world population. We identify treatment patterns associated with radium-223 and link these patterns with time to skeletal related event (SRE) and mortality. Methods: We reviewed charts of all men with diagnosed with mCRPC in the entire Veterans Affairs (VA) system alive as of January 1, 2013 who received radiun-223. We generated Kaplan Meier curves for survival and time to SRE based on treatment patterns. We examined the association between common treatment patterns and mortality and time to SRE with Cox models. Results: We identified 318 men with bone mCRPC who received radium-223. Median age at radium start was 69 ys and median follow up was 25.3 months. Median survival was 11 months. 277 patients died during the study period (87%). 50% (158/318) completed ≤4 injections. There was a significant difference mortality among four consolidated treatment patterns (p=0.005) and but no difference SRE (p=0.10). On univariable and multivariable analysis, men who received AR target + docetaxel + radium-223 had increased mortality vs. men who received AR target + radium-223 (p=0.010 and 0.005, respectively). Multivariable analysis showed that non-black race, bone pain, SRE prior to radium, and higher PSA were all linked with worse mortality. Conclusions: We described the largest known cohort of men in the real world who received radium-223. We identified common treatment patterns with differing risk for overall mortality. Further prospective studies are needed to better understand whether differences in survival are attributed to worsening disease status requiring more aggressive therapy, lead-time bias, or true differences in treatment efficacy.
Outcomes of high-dose whole pelvic simultaneous integrated boost IMRT in patients with pelvic lymph node-positive prostate cancer.
Authors: Mizowaki Takashi , Takayama Kenji , Nakamura Kiyonao , Aizawa Rihito , Inoue Takahiro , Yamasaki Toshinari , Kobayashi Takashi , Akamatsu Shusuke , Ogawa Osamu
Published: March 2019

192

Background: Managements of prostate cancer patients with positive pelvic lymph node (N1M0) have been very challenging. We evaluated the outcomes of high-dose whole pelvic (WP) intensity-modulated radiation therapy (IMRT) by using the simultaneous integrated boost (SIB) technique, combined with long-term androgen deprivation therapy (ADT). Methods: Between May 2005 and November 2013, 52 patients with T2a-T4N1M0 prostate cancer were definitively treated by WP SIB-IMRT. Pelvic lymph node metastases were clinically diagnosed based on the following criteria; depicted swollen lymph nodes on diagnostic imaging associated with subsequent shrinkage in size on a follow-up imaging after neoadjuvant ADT (NA-ADT). The median age and initial PSA value were 66 years old (range: 52–79) and 29.7 ng/ml (4.8–251.9), respectively. NA-ADT (median: 8 months, range: 5–20) was given in all cases. SIB WP-IMRT was designed to simultaneously deliver 78 Gy, 66.3 Gy, and 58.5 Gy in 39 fractions to the prostate plus seminal vesicles, metastatic lymph nodes, and the pelvic lymph node region, respectively. Adjuvant ADT (A-ADT) was given in all patients except for one case who developed severe adverse events during NA-ADT. In 9 patients, permanent A-ADT was given due to castration after IMRT (n = 2) and development to castration resistant status during A-ADT (n = 7). The median duration of A-ADT was 24 months (range: 7–71) in the remaining 42 patients. Results: The median follow-up period was 69 months (range: 12–136). Biochemical relapse-free survival rate based on the Phoenix definition and distant metastasis-free survival rates at 5 years were 69% (95% CI = 54%–80%) and 78% (95% CI = 64%–87%), respectively. Overall survival and prostate cancer-specific survival rates at 5 years were 88% (95% CI = 74–94%) and 92% (95% CI = 79–97%), respectively. Loco-regional recurrence was not observed. 5-year cumulative incidence rates of grade 2-3 late GU and GI toxicities were both 2%. No grade 4 acute or late toxicity was observed. Conclusions: High-dose WP SIB-IMRT to patients with N1M0 prostate cancer seems promising, and warrants future prospective studies.
The Veterans Health Administration Precision Oncology Program for Advanced Prostate Cancer Patients: Expanding tumor NGS opportunities to a broader patient population.
Authors: Sokolova Alexandra , Cheng Heather H. , Hintze Bradley J , Kelley Michael J. , Spector Neil L , Duffy Jill , Lynch Julie Ann , Rettig Matthew , Montgomery Robert B.
Published: March 2019

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Background: Progress in understanding molecular changes in advanced prostate cancer has led to promising precision oncology opportunities; to date, most have been concentrated at tertiary research centers and urban centers and unequally available to patients. The VHA is the largest integrated healthcare system in the U.S. and provides medical care to >6 million veterans (~40% living in rural areas). The VHA has implemented a system-wide National Precision Oncology Program (NPOP) to offer tumor NGS testing to veterans with cancer. Methods: VHA patients with advanced stage cancers were offered targeted NGS gene panels (Personalis ACE Extended Cancer Panel; PGDx CancerSELECT/PlasmaSELECT) as part of clinical care. Annotated sequence data is collected by NPOP. We report preliminary findings of the participating veterans with prostate cancer. Results: 372 veterans from 81 sites underwent NGS sequencing of their prostate tumors (n=311) or cfDNA (n=61). Tumors from 165 (44%) were found to have mutations (allelic ratio ≥5%) in 47 genes. Of 372, 62 harbored mutations in TP53 (17%), 9 in NOTCH1 (2%), 16 in PTEN (4%), 16 in AR (4%), 13 in ATM (4%), 11 in BRCA2 (3%), 2 in MSH2 (0.5%), 1 in NBN (0.3%), and 1 in PALB2 (0.3%). 7 men (1.8%) had adequate tumor, but no identifiable somatic mutations. NPOP findings were compared to the existing databases SU2C/PCF (of metastatic biopsies in metastatic castration resistant disease) and TCGA (of primary tumors in localized disease), see table. Findings will be updated at presentation. Conclusions: The VA NPOP has been successfully implemented, and prostate tumors from veterans were found to carry potentially actionable mutations, including BRCA2 and ATM, for which there are precision treatment trials. The program will be expanded and will facilitate more diverse and equitable distribution of access to precision oncology diagnostics and therapeutic opportunities, in alignment with the Cancer Moonshot Initiative. (e.g. VA-ABCD clinicaltrials.gov; NCT02985021). [Table: see text]
Next Generation Sequencing (NGS) in metastatic castration resistant prostate cancer (mCRPC) to identify targets for individualized treatment: Is it feasible in daily routine?
Authors: Heidenreich Axel , Pfister David A. , Odenthal Margarete , Nestler Tim , Büttner Reinhard
Published: March 2019

194

Background: Systemic of mCRPC consists of various approaches such as docetaxel, abiraterone, enzalutamide, Radium-223 and cabazitaxel. If all treatment options are exhausted, molecular profiling of biopsies from progressive metastases might enable an individualized approach with targeted therapies. It was the purpose of our study to examine (1) the feasibility of NGS in daily routine, (2) the frequency of treatable mutations and (3) the therapeutic outcome. Methods: From 1/2016 to 12/2017, 214 patients with mCRPC were treated; 52 pts progressed after exposure to all approved systemic therapies. All men underwent biopsies of the progressing lesions to perform mutational analysis via NGS using 9 Multiplex PCR amplicons (AR, ATM, BRCA1/2, CTNNB1, DLL3, PIK3CA, PTEN, RAD51C, TP53) which generation was done with a GeneRead DNAseq Custom Panel V2 (Qiagen). Creation of the library was done with the use of GeneRead DNA Library I Core, GeneRead DNA I Amp Kits and NEXTflex-96 DNA Barcode Adapter. Results: Following lesions were biopsied n = 8 (15.4%) liver, N = 4 (7.7%) lung, n = 4 (7.7%) bone, n = 36 (69.2%) lymph node. Sufficient material was received in all cases. 31 (59.7%) demonstrated wild type in all amplicons vorhanden, n = 21 (40.3%) demonstrated at least 1 potentially treatable mutation: BRCA1/2 or ATM n = 11, AR n = 7, DLL3 n = 3, p53 n = 9, Rad51C n = 4, CTNNB1 n = 4, PTEN/PIK3CA n = 4. Results were discussed in our molecular and clincical phase-I tumor board. Median overall survival oft he pateint cohort is 18.5 (6-34) months. Conclusions: NGS analysis of biopsy samples from progressing metastatic sites is feasible in mCRPC presuming an interdisciplinary setting in the diagnostic and therapy decision making process. NGS results in the identification of treatable mutations in more than one third of patients.
Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).
Authors: Fu Simon Yuen Fai , Ritch Elie , Yip Steven , Khalaf Daniel , Taavitsainen Sinja , Annala Matti , Vandekerkhove Gillian , Kushnir Igal , Hotte Sebastien J. , Ferrario Cristiano , Wyatt Alexander William , Chi Kim N.
Published: March 2019

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Background: A small proportion of metastatic PC exhibit outlier somatic mutation rates. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing of 1047 plasma cell-free DNA samples and calculated somatic mutation burden. HM samples and available matched archival tissue were additionally subjected to whole exome sequencing. Trinucleotide mutational signatures and microsatellite instability (MSI) were determined via nonnegative matrix factorization and mSINGS, respectively. We evaluated PSA decline ≥50% from baseline (PSA50), time from androgen deprivation therapy (ADT) to castration-resistant prostate cancer (CRPC), median duration of 1st line CRPC therapy (1L CRPCT) and median OS (time from CRPC to death). The control cohort consisted of 199 CRPC pts treated with 1L abiraterone + prednisone (ABI+P) or enzalutamide (ENZ). Results: 671 samples from 434 pts had ctDNA% > 2 and were evaluable. The median mutation rate was 2.59/Mb (range, 0.9 – 155.6/Mb). 32 samples from 24 pts had > 11/Mb and fell above the 95th percentile for mutational burden. 10/24 pts had biallelic loss of mismatch repair (MMR) genes MSH2/6, and a further 5 pts without confirmed MMR defects had enrichment of trinucleotide signatures associated with MMR and/or were MSI high by mSINGS. The remaining 9 pts had either BRCA2 mutations or Kataegis (localized hypermutation). Clinical data was available for 10/15 MMR defective pts. Median age was 73.6 y. At diagnosis, 70% had Gleason score ≥8, 50% with M1 disease, median PSA was 22.8 (6.8 – 820). PSA50 with ADT (n = 8) or ADT + docetaxel (n = 2) was 100% in the castration sensitive setting. 5 pts had ENZ, 4 ABI + P, and 1 cabazitaxel in 1L CRPCT. Comparing the MMR defective with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9 – 11.4) vs. 18.2 m (95% CI 15.1 – 21.3), p = 0.001; 1L CRPCT duration was 3.9 m (95% CI 1.3 – 6.5) vs. 8.4 m (95% CI 7.2 – 9.6), p = < 0.001; median OS was 13.1 m (95% CI 0.33 – 25.9) vs. 40.1 m (95% CI 32.4 – 47.8), p < 0.001. Conclusions: HM and MMR defects can be identified in a liquid biopsy. Although these pts can have poor outcomes with standard therapy, ctDNA may help selection for immunotherapy.
Toxicity results from a novel phase I/II trial of VMAT radiotherapy to prostate and pelvic nodes plus six cycles of radium-223 in mCSPC metastatic to bone post ADT and docetaxel.
Authors: O'Sullivan Joe , Turner Philip Geoffrey , Jain Suneil , Hounsell Alan R. , Mitchell Darren M. , Biggart Sandra , Grey Arthur , Cole Aidan
Published: March 2019

196

Background: Recent data has shown an overall survival (OS) benefit for up front Docetaxel or Abiraterone combined with androgen deprivation therapy (ADT) in metastatic castration sensitive prostate cancer (mCSPC). Data from STAMPEDE also suggests an additional OS benefit for radiotherapy to the prostate in men with low volume metastases. We hypothesised that Radium-223 + Radiotherapy to prostate and pelvic nodes following docetaxel (DOC) would be well tolerated and potentially improve OS in men with mCSPC involving bone. Methods: Men with mCSPC involving bone were treated in a single arm phase 1/2 study in which they received radical dose radiotherapy (74Gy/37) to prostate and pelvic nodes using Volumetric Modulated Arc Therapy (VMAT) radiotherapy and 6 cycles of Radium-223, 55kBq/kg following up front ADT and DOC. The primary endpoint was toxicity with secondary endpoints including time to PSA and ALP progression and radiological response. Results: We report the results of 27 men, median age 67 years treated in the study with a median follow up of 25 months post 1st ADT. 81% of men had high volume disease. The schedule was well tolerated with grade ≥3 toxicity occurring in 5 patients (18.5%). Most toxicity was short lived thrombocytopenia and leucopenia. No unexpected toxicity was observed. All but 2 patients received all 6 cycles of Radium-223. One patient died of progressive disease before completion of the course of Radium-223. To date, 6 out of 27 patients have died, actuarial survival at 24 months is 83%. To date 9 out of 27 (33%) patients have developed PSA progression. Only 1 patient had a progressive alkaline phosphatase levels during the course of Radium-223 treatment. Conclusions: In men with mCSPC involving bone, a schedule of radical dose radiotherapy to prostate and pelvis + 6 cycles of Radium-223 is well tolerated post ADT + DOC. This treatment schedule will now join as a new arm of the STAMPEDE trial with OS as primary endpoint. Clinical trial information: 2014-000273-39.
A randomized trial comparing fluorocholine-PET/CT with conventional imaging in prostate cancer.
Authors: Williams Scott , Beauregard Jean-Mathieu , Roselt Peter , Moody Kate , Fisher Richard , Drummond Elizabeth , Hicks Rodney J
Published: March 2019

2

Background: We conducted a randomised trial comparing 18Flourocholine-PET/CT (FCH) to Computed Tomography (abdomen and pelvis) plus 99mTc-Whole Body Bone Scan (Conventional Imaging [CIm]) to determine imaging performance in prostate cancer (PC). Methods: This prospective two-arm 1:1 randomised trial enrolled men with newly diagnosed or biochemically recurrent PC to first-line imaging (FLI) with either CIm or FCH. Participants without evidence of metastases proceeded to second-line imaging (SLI) using the alternative imaging strategy. The primary aim was to determine whether FCH was more effective as a FLI approach in changing management. Secondary endpoints included incremental utility of SLI and negative predictive value (NPV) based on progression-free survival (PFS). Australian New Zealand Clinical Trials Registry ACTRN12608000641392. Results: 108 men were enrolled; 44% were for staging of newly-diagnosed PC and median follow-up 43 months. Imaging impacted clinical management in 32.4% of men (95% CI=23.7-42.1%), mostly with FLI (n=30). High-impact management changes occurred in 27.8% (95% CI=16.5-41.6%) of FCH cases compared with 11.1% (95% CI=4.2-22.6%) in the CIm arm (p=0.032). The final management plan was derived using FCH in 98.1% (95% CI = 90.1-100%) of cases and 92.6% (95%CI = 82.1-97.9%) of CIm cases (p=0.242). FLI with FCH showed unequivocally N1 or M1 disease in 22.2% (95% CI = 12-35.6%), and 16.7% (95% CI = 7.9-29.3%; p= 0.531) of CIm cases. The overall NPV for stage TxN0M0 (from all imaging) was 26.3% (95% CI: 13.9 - 41.2%), with no significant difference between arms (p=0.9). For N1M0 cases, the NPV was 14.3% (95% CI: 7.1 - 35.7%). The identification of N1M0 by FCH resulted in a longer time to identification of progressive disease, with a median PFS of 32 months (95% CI=2-68months) compared with 3 months (95% CI=1-16 months) in the CIm N1M0 cohort (p=0.05). Conclusions: FCH-PET/CT identifies more high-clinical-impact lesions than CIm as first-line imaging. All imaging modalities were poor at predicting subsequent progressive disease. Isolated node-positive disease seen with FCH is associated with a longer time to - but similarly high rates of - recurrence, suggesting a lead-time bias. Clinical trial information: ACTRN12608000641392.
Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): Preliminary results of GALAHAD.
Authors: Smith Matthew Raymond , Sandhu Shahneen Kaur , Kelly William Kevin , Scher Howard I. , Efstathiou Eleni , Lara Primo , Yu Evan Y. , George Daniel J. , Chi Kim N. , Summa Jason , Kothari Nishi , Zhao Xin , Espina Byron M. , Ricci Deborah S. , Simon Jason S. , Tran Namphuong , Fizazi Karim ,   GALAHAD Investigators
Published: March 2019

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Background: New therapies are needed for patients (pts) with mCRPC progressing after androgen-receptor signaling inhibitors (ARSIs) and taxane therapies. Niraparib is a once daily highly selective inhibitor of poly (ADP-ribose) polymerase (PARP-1 and 2). Methods: GALAHAD is an ongoing open label Ph 2 study assessing niraparib (300 mg daily) in pts with DRD progressing on/after ARSIs and taxane chemotherapy. Using a validated plasma assay, DRD status was defined as pathogenic mutations (including homozygous deletions) of BRCA1/2, ATM, FANCA, PALB2, CHEK2, BRIP1 or HDAC2. Composite response rate (RR) was defined as an objective response by RECIST 1.1 for measurable disease, circulating tumor cell (CTC) conversion to < 5/7.5 mL blood or prostate-specific antigen (PSA) decline of ≥50% (PSA50). Here, preliminary data on RR and adverse events (AEs) are reported in pts with biallelic DRD. Results: As of 10 Sep 2018, 123 pts with mCRPC and DRD were enrolled, of whom 39 had biallelic DRD (23 BRCA1/2). The median follow-up was 5.7 mo (2.0–23.7). Table depicts RRs for pts with biallelic DRD by BRCA status. Composite and objective RRs were 65% and 38% in pts with biallelic BRCA1/2, respectively. 3/8 pts (38% [2/5 BRCA1/2 and 1/3 non-BRCA]) with measurable visceral metastases showed objective response. Among the 20 biallelic responders, the duration of treatment (tx) has exceeded 4 mo in 13 pts and 6 mo in 8 pts; 14 pts remain on tx. The most common grade 3/4 hematologic AEs were anemia (25%) and thrombocytopenia (15%) (manageable by dose reduction/interruption). The most common grade 3/4 nonhematologic AEs were asthenia (6%) and hypertension (5%). Conclusions: These results suggest niraparib has compelling activity as monotherapy for pts with treatment-resistant mCRPC, particularly those with biallelic BRCA1/2 identified by a blood assay. Clinical trial information: NCT02854436. [Table: see text]
Association of serum androgen and drug levels with response to abiraterone.
Authors: Mostaghel Elahe A. , McKay Rana R. , Cho Eunpi , Zhang Zhenwei , Marck Brett , Matsumoto Alvin M. , Sharifi Nima , Taplin Mary-Ellen , Nelson Peter , Montgomery Robert B.
Published: March 2019

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Background: The association of serum ABI and androgen levels with clinical efficacy in men with CRPC is not well understood. Methods: We measured androgens, ABI and its key metabolites (D4A and 5α) in serum at 4, 8, and 12 weeks (wks) in 29 men with CRPC treated with ABI (for associations with PSA response and time to radiographic progression (TTP)); in 58 men from a study of ABI without prednisone; and in 22 men with localized PCa treated with neoadjuvant ABI for 3 months prior to definitive therapy (including prostate levels). Results: Median (Med) TTP was 36 mo (4-104). 52% had a PSA response (decline >30% at wk12), and 34% early progression (TTP < 6 mo). There was no difference in ABI (at wk4 or average of wks 4/8/12) in men with v without PSA response, or in men with early v late TTP. D4A and 5α at wk4 were higher in early v late progressors (2.9 v 1.5 ng/ml, p=0.05; 10.35 v 6.7 ng/ml, p=0.08). TTP was longer in the lowest v highest quartile of drug levels (ABI: 4wk 48 v 30 wks; 8wk 60 v 16 wks; D4A: 4wk 40 v 16 wks; 8wk 60 v 28 wks; 5a: 8wk 41 v 16 wks, p<0.05 all). The lowest quartile of pre-ABI androgens had shorter TTP (DHEAS 24 v 52 wks; T 30 v 52 wks, p<0.05 both). In both CRPC studies, men with pre-ABI DHEAS > Med had 2-5x higher levels of all steroids (DHEAS 110 v 22 ug/dl, DHEA 184 v 49 ng/dl, AED 46 v 26 ng/dl, and T 9 v 4.9 ng/dl, p<0.05 all). While markedly suppressed by ABI in both groups, levels remained detectable and higher in the ‘high’ group (DHEAS 5.4 v 1.6 ug/dl; DHEA 1.3 v 0.6 ng/dl; p<0.05 both) regardless of ABI levels (37.4 ng/ml, 2.75-89; 36.8 ng/ml, 8.7-121, p=ns). Androgens in serum and prostate after neoadjuvant ABI were higher in men with pre-ABI eugonadal serum DHEAS levels > v < Med, regardless of serum or tissue ABI levels on treatment. Conclusions: In men with pre-ABI serum DHEAS < Med, androgens were suppressed even at low serum ABI levels, whereas in men with pre-ABI DHEAS > Med, levels were not completely suppressed even at high ABI levels, explaining the minimal impact of dose escalated ABI and observed noninferiority of low dose ABI previously reported in men with CRPC. The shorter TTP in the highest quartiles of ABI, D4A and 5α may reflect increased conversion to the AR agonist metabolite 5α. Men with pre-ABI DHEAS > Med may warrant stratification to more potent/combination therapy. Clinical trial information: NCT01503229.
Positron emission tomography with 18F-fluciclovine to predict recurrence in post-treatment recurrent prostate cancer and its role in altering treatment plans.
Authors: Chong Julio , Muhleman Mitchel , Say Rollin , Kostakoglu Lale , Ahmed Jalal , Tewari Ashutosh , Stock Richard , Oh William K.
Published: March 2019

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Background: 18F-fluciclovine PET/CT can improve the detection of post-treatment recurrent prostate cancer (PCa). We quantified factors which increase the likelihood of a positive scan, assessed the ability of 18F-fluciclovine to alter treatment plans and identified an optimal PSA cut-off to identify radiographic recurrence. Methods: Patients who received 18F-fluciclovine PET/CT for recurrent PCa (n=78) were analyzed. Treatment changes based on positive scans were tracked. A receiver-operator characteristic (ROC) curve was used to estimate the optimal PSA cut-off for a positive scan. Results: 18F-fluciclovine predicted radiographic recurrence in 67.9% of patients. PSA at scan (p = 0.010), salvage therapy (p = 0.03), any use of ADT (p = 0.016) and number of studies (p = 0.042) were all associated with a positive scan. Alteration of treatment plans occurred in 34/58 (58.6%) patients. Recurrence sites are: 79/120 (65.8%) lymph nodes, 27/120 (22.5%) bone, 11/120 (9.2%) prostatic bed, and 3/120 (2.5%) elsewhere. The most common treatment alteration was directed stereotactic body radiation therapy (SBRT) (16/34, 47%), followed by salvage surgical therapy (4/34, 11.7%) and ADT (3/34, 8.7%).The optimal PSA cut-off was 0.5 with sensitivity of 81.13% and specificity of 78.38% (ROC=0.7880). Conclusions: 18F-fluciclovine PET/CT detected radiographic disease in 67.9% of patients, resulting in alterations in treatment plans in 58.6% of cases. SBRT was the most common alteration in treatment plan. Previous use of salvage therapy or ADT are risk factors and when combined with a PSA >0.5, may be associated with radiographic recurrence. [Table: see text]
Morphology-predicted, large-scale transition (LST) number in circulating tumor cells (CTC) as a biomarker of chromosomal instability (CIN) to assess early resistance to standard of care (SOC) drugs in mCRPC.
Authors: Scher Howard I. , Schonhoft Joseph , Hullings Melanie , Carbone Emily , Barnett Ethan , Sutton Ramsay , Jendrisak Adam , Landers Mark Andrew , Wang Yipeng , Dittamore Ryan
Published: March 2019

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Background: CIN is a mechanism by which tumor cells evolve, adapt, and evade therapeutic insults. We explored the relationship between the presence of LST as a biomarker of CIN through distinct CTC phenotypes, and sensitivity of tumors with the biomarker to standard of care (SOC) drugs. Methods: CTCs from 634 mCRPC blood samples were morphologically characterized by the Epic Sciences platform [Cytokeratin, CD45, DAPI, Androgen Receptor (AR) staining]. Training: 20 digital single cell image features were extracted from 608 CTC images from 26 patients (Pts) and single cell sequenced to determine the number of genomic LSTs. An image feature based algorithm to predict whether the number of LSTs was above the normal range defined by analysis of leukocytes was trained using this cohort (pLST) and parameters were locked. Analytical Validation (AV): the pLST algorithm was applied to a separate cohort of 570 CTCs from 54 Pts that were also sequenced to test single cell analytical performance. Clinical Validation: The pLST algorithm was then applied to CTC detected in 554 Pt samples obtained at prior to (BL, n= 324) and matched on-therapy (OnTx, n= 230) ~1 mo after starting SOC [including AR directed Tx and taxane]. A pre-defined patient scoring of > 3 pLST+ CTC/mL was related to PSA kinetics, time on drug, and overall survival (OS). Results: pLST identifies CTCs with a high number of genomic LSTs. Pts with pLST+ at BL or OnTx had poor survival (see table): 12/13 pts receiving ARSi’s and 17/18 pts receiving taxanes who were pLST+ On-Tx required a change of Tx in a median of 1.3 mo (0.9 to 2.1) or died within 6 mo. Conclusions: CTC morphology can be used to predict CIN as defined by high LSTs. CTC pLST is a strong marker of resistance to SOC Tx in mCRPC pts and treatment failure requiring a change in Tx earlier than standard criteria.[Table: see text]
Tumor testing in men with prostate cancer to predict for germline DNA-damage repair mutations.
Authors: Carlo Maria Isabel , Kemel Yelena , Breen Kelsey , Cadoo Karen Anne , Walsh Michael Francis , Abida Wassim , Autio Karen A. , Danila Daniel Costin , Kampel Lewis J. , Morris Michael J. , Rathkopf Dana E. , Slovin Susan F. , Solit David B. , Offit Kenneth , Stadler Zsofia Kinga , Scher Howard I. , Robson Mark E.
Published: March 2019

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Background: Current guidelines recommend genetic testing for patients (pts) who have BRCA1/2 mutations on tumor-only testing, where germline is not subtracted. The clinical utility of this approach, and possible inclusion of other DDR genes associated with cancer susceptibility, has not been examined in men with prostate cancer. Methods: Pts with mostly advanced prostate cancer were prospectively enrolled to a matched tumor-germline DNA sequencing protocol and consented for disclosure of germline results. Germline analysis was done with an institutional, CLIA-certified next generation sequencing (NGS) platform (MSK-IMPACT) and analyzed for likely pathogenic or pathogenic germline mutations in at least 76 cancer susceptibility genes. Clinical data was retrieved from the medical record. We report on the frequencies in the germline and in the tumor of a subset of DDR genes. Results: 1243 men had analysis of both germline and tumor. Median age 64 (range 35-90). 12% had a second malignancy and 40% reported a relative with prostate cancer. 19% were of Ashkenazi Jewish (AJ) descent. 330 (27%) had any mutation in BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, MSH2, MSH6, MLH1, PMS2. 127 (10%) had a germline mutation, of which 36% were AJ founder mutations. For each gene, the percentage of mutations found in germline and tumor is shown in the table. Conclusions: Of prostate cancer pts found to have any DDR mutation on tumor-germline testing, 29% had a germline mutation. Proportion of germline mutations was highest for PALB2, CHEK2 and BRCA2. These findings not only support germline testing when BRCA1/2 mutations are found tumor-only sequencing, but also support germline testing when other DDR mutations are seen. Clinical trial information: NCT01775072. [Table: see text]
SPINK1 expression and outcomes postprostatectomy in race-specific cohorts.
Authors: Faisal Farzana A , Kaur Harsimar B , Tosoian Jeffrey J. , Tomlins Scott A. , Schaeffer Edward M. , Lotan Tamara L.
Published: March 2019

23

Background: The SPINK1 molecular subtype has been shown to be more common in African American (AA) men with prostatic adenocarcinoma (PCa) than European Americans (EA). Other studies have suggested that SPINK1 expression is associated with more aggressive disease. However, there have been limited studies examining clinical outcomes by SPINK1 status in racially diverse cohorts. Methods: The objective was to determine the associations between SPINK1 subtype, race, and clinical and pathologic outcomes after radical prostatectomy (RP). A total of 186 AA and 206 EA men who underwent RP at Johns Hopkins were matched according to pathologic Gleason grade. We examined SPINK1 status by immunohistochemistry on tissue microarrays using a genetically validated assay. ERG and PTEN were assessed previously using validated immunohistochemistry assays. SPINK1 prevalence was compared between races. Logistic regression and Cox proportional hazard analyses assessed the association of SPINK1 status with pathologic and oncologic outcomes in race-specific multivariate models. Results: SPINK1-positive subtype was present in 25% (45/186) of AA and 15% (30/206) of EA men (p = 0.013). SPINK1 expression was generally mutually exclusive with ERG expression and PTEN loss in both racial cohorts. There were no differences in pathologic grade group (GG), pathologic stage, biochemical recurrence (BCR)-free survival, or metastasis-free survival between SPINK1-positive and SPINK1-negative tumors in the overall cohort or by race. In multivariable analyses, SPINK1 expression was not associated with BCR (AA: HR 0.99, 95% CI 0.56-1.75, p = 0.976; EA: HR 0.88, 95% CI 0.43-1.77, p = 0.720) or metastasis (AA: HR 0.79, 95% CI 0.25-2.49, p = 0.691; EA: HR 1.55, 95% CI 0.58-4.11, p = 0.381) in either the AA or the EA cohort. Conclusions: SPINK1-positive subtype is more prevalent in AA than EA men with PCa. While previous studies showed that SPINK1 may be associated with more aggressive PCa, we found that SPINK1 protein expression was not associated with worse pathologic or oncologic outcomes including BCR and metastasis after RP in either AA men or EA men.
Clinical validation of circulating cytokines as markers of prognosis and response to docetaxel in men with metastatic castration-resistant prostate cancer.
Authors: Mahon Kate Lynette , Lin Hui-Ming , Lee-Ng Michelle , Stockler Martin R. , Gurney Howard , Mallesara Girish , Briscoe Karen P. , Marx Gavin M. , Higano Celestia S. , De Bono Johann S. , Chi Kim N. , Brown David , Breit Samuel N. , Horvath Lisa
Published: March 2019

230

Background: Elevated circulating macrophage inhibitory cytokine -1 /growth differentiation factor 15 (MIC-1/GDF15), interleukins 4 (IL4) and 6 (IL6) levels were associated with poor prognosis and resistance to docetaxel chemotherapy in an exploratory cohort of men with metastatic castration resistant prostate cancer (mCRPC). To establish level 2 evidence of biomarker utility, these cytokines were tested in internal and external validation cohorts. Methods: Internal validation cohort: Plasma samples taken at baseline (BL) and preC2 docetaxel (n = 120). MIC-1/GDF15, IL-4 and IL-6 measured by ELISA assay. External validation cohort: Serum samples taken at BL and/or preC3 docetaxel in 430 men with mCRPC on phase III SYNERGY study (docetaxel +/- custirsen as 1st line chemotherapy in mCRPC with no OS benefit in the experimental arm). MIC-1/GDF15 measured by ELISA assay. Associations between cytokine levels, PSA response, time to PSA progression and OS were assessed by non-parametric tests and Cox Regression survival analyses. Results: Internal validation: At a median follow-up of 14 months, higher MIC-1/GDF15 levels at BL and preC2 were associated with shorter OS (BL; HR 1.2 95%CI 1.0-1.4; p = 0.03 and preC2; HR 1.3 95%CI 1.1-1.5; p = 0.004). Increase in MIC-1/GDF15 after chemotherapy correlated with lack of PSA response (p < 0.001). IL4 and IL6 did not correlate with survival or demonstrate additional value. External validation: At a median follow-up of 23 months, higher MIC-1/GDF15 levels at BL and preC3 predicted shorter OS (BL; HR 1.4 95%CI 1.2-1.6; p < 0.0001 and preC3; HR 1.6 95%CI 1.3-1.8; p < 0.0001). Higher pre C3 MIC-1/GDF15 levels were also associated with shorter time to PSA progression (HR 1.2 95% CI 1.0-1.4; p = 0.02). Rise in MIC-1/GDF15 from BL to preC3 correlated with lack of 50% PSA fall at 12 weeks (p < 0.001). Conclusions: Adherence to a biomarker development pipeline provides level 2 evidence of the prognostic value of circulating MIC-1/GDF15 in men with mCRPC receiving docetaxel. A prospective biomarker led study is now necessary to establish clinical utility.
Predictors of positive lesions in 18F-fluciclovine PET/CT.
Authors: Hougen Helen Y , Mallak Nadine , Chen Yiyi , Degnin Catherine , Kopp Ryan P , Liu Jen-Jane , Isharwal Sudhir , Hung Arthur
Published: March 2019

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Background: The 18F-Fluciclovine (FACBC) PET/CT scan has higher sensitivity than traditional imaging modalities for detection of prostate cancer (PCa) recurrence. We aim to identify the PSA characteristics as predictors of positive FACBC scan. Methods: Seventy-eight patients who underwent FACBC scan in 2018 at our institution were identified. Patient demographics, prior PSA, clinical information including prior treatment was recorded. Scans were deemed positive if definitive lesions were noted at the prostate bed, pelvic lymph nodes, or skeletal level. Detection rate was the ratio of positive over total scans and was calculated for PSA ranges. PSA velocity (PSAV) was calculated for patients who did not initiate androgen-deprivation therapy 12 months prior to the scan. The baseline PSA and PSAV were modeled as predictors of having a positive scan using logistic regression. Results: The median baseline PSA is 2.7 (range 0.2 - 226.5). The rates of positivity increased with increasing baseline PSA (Table 1). Positive scans had higher median baseline PSA (3.0, range 0.2-226.5 vs. 1.2, range 0.2-26.0; p = 0.0015) and higher PSAV (median 2.3, range -0.6-1478.7 vs. 1.0, range -0.5-31.9; p = 0.025). Baseline PSA (AUC = 0.712) was better predictor than PSAV (AUC = 0.656) of a positive scan. Combining the two variables does not improve their predictive ability (AUC = 0.719). There is a 50% detection rate in post-radical prostatectomy (RP) patients (Table 2). Conclusions: FACBC PET’s detection rate increases with increasing baseline PSA. While higher PSAV is associated with higher rate of positive scan, it did not increase the predictive ability of baseline PSA for a positive scan in prostate cancer recurrence patients. [Table: see text][Table: see text]