bluuebunny/crossref_metadata_2025 huggingface dataset:
Definitive radiation therapy and survival in clinically node-positive prostate cancer.
Authors: Alex Bryant , Kader A. Karim , McKay Rana R. , Einck John Paul , Mell Loren K. , Mundt Arno James , Kane Christopher J. , Efstathiou Jason A. , Murphy James Don , Rose Brent Shane
Published: February 2018

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Background: The survival benefit of combined radiation therapy (RT) and androgen deprivation therapy (ADT) compared to ADT alone for clinically lymph node-positive prostate cancer remains controversial. Methods: We identified clinically node-positive, non-metastatic prostate cancer patients diagnosed between 2000-2015 and treated with ADT (n = 450) or ADT/RT (n = 198) from a national Veterans Affairs database. We compared prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) between treatment groups using multivariable Cox regression, controlling for potential confounders. All tests of statistical significance were two sided. Results: Compared to ADT alone, ADT/RT was associated with improved ACM (hazard ratio [HR]: 0.56, 95% CI 0.41-0.76, p < 0.001) and PCSM overall (HR 0.65, 95% CI 0.43-0.97, p = 0.03). We noted a significant interaction between ADT/RT and pre-treatment PSA for PCSM (p for interaction = 0.005) and ACM (p for interaction < 0.001). ADT/RT was associated with improved PCSM among patients with PSA less than (HR 0.43, 95% CI 0.24-0.78, p = 0.004) but not greater than the median of 26 ng/mL (HR 1.01, 95% CI 0.60-1.71, p = 0.96). ADT/RT was also associated with improved ACM among patients with PSA less than (HR 0.38, 95% CI 0.25-0.57, p < 0.001) but not greater than the median (HR 0.91, 95% CI 0.60-1.38, p = 0.66). Conclusions: Definitive treatment with ADT/RT is associated with improved ACM and PCSM among patients with clinically node-positive prostate cancer. The survival benefit of ADT/RT is only apparent among patients with lower baseline PSA. Patients with clinically node-positive disease appear to be a heterogeneous cohort, with a subset that may achieve long-term survival with combined radiation and androgen deprivation therapy.
DNA repair gene panel mutations in young onset prostate cancer cases in the.
Authors: Eeles Ros A. , Leongamornlert Daniel , Saunders Ed , Wakerell Sarah , Whitmore Ian , Dadaev Tokhir , Borrella Clara Cieza , Govindasami Koveela , Brook Mark , Lophatananon Artitaya , Muir Kenneth , Conti David V , Kote-Jarai Zsofia
Published: February 2018

18

Background: Prostate cancer (PrCa) is the most common solid tumour in men in the Western world. There is substantial evidence that PrCa predisposition is due both to common and rare germline variation. Methods: We screened 167 genes from DNA damage response and repair pathways, within a UK based cohort of young onset cases (diagnosed at < 65 years) and controls. Samples were sequenced using a custom Agilent SureSelectXT bait library and Illumina HiSeq technology and processed using a BWA/GATK 2.8 pipeline. Following sample QC, data were analysed from 1,285 PrCa cases and 1,163 controls. Results: We identified 5,086 single nucleotide variants (SNVs) and 175 indels; 233 unique protein truncating variants (PTVs) with MAF < 0.5% in controls were found in 97 genes of the screening panel. The total proportion of PTV carriers in cases was higher than in controls (14.5% vs. 11.6%, P = 0.036; OR = 1.29, 95% CI 1.01-1.64). This enrichment was greater within the previously reported BROCA gene set of 22 tumour suppressor genes (4.5% vs 2.2%, P = 2.5x10-3; OR = 2.07, 95% CI 1.28-3.34). To identify genes which best to distinguish PrCa cases from controls, we applied the adaptive combination of P values algorithm, ADA, for genes with at least 2 carriers of PTVs. This analysis selected 10 genes, (OR = 3.37, 95% CI 2.05-5.66, PADA= 5.99x10-3); men with PTVs in these were about 3.4-fold more likely to have PrCa (5.8% vs. 1.8%). We subsequently compared aggressive cases (Gleason score ≥ 8, n = 204) with non-aggressive cases (Gleason score ≤ 7, n = 1049) and lethal PrCa cases (cause of death PrCa, n = 183) with indolent cases (Gleason score ≤ 6, n = 563) to evaluate genes associated with poor clinical prognosis. Using ADA, 4 genes were selected for aggressive PrCa ( PADA= 0.006) and 2 of these also for lethal PrCa ( PADA= 0.057). Conclusions: These gene sets provide an 11 gene panel which could be used for clinical testing and will help to facilitate the development of a PrCa specific sequencing panel with both predictive and prognostic potential.
Abiraterone acetate (AA) plus prednisone (P) 5 mg QD in metastatic castration-naïve prostate cancer (mCNPC): Detailed safety analyses from the LATITUDE phase 3 trial.
Authors: Fizazi Karim , Tran Namphuong , Fein Luis Enrique , Matsubara Nobuaki , Bjartell Anders , Galli Luca , Lee Jae-Lyun , Mazhar Danish , North Scott A. , Olmos David , Suttmann Henrik , Zou Qing , Li Susan , Martin Jason L. , Park Youn C. , Sulur Giri , Deprince Kris , De Porre Peter , Chi Kim N.
Published: February 2018

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Background: AA + P added to androgen deprivation therapy (ADT) improves overall survival (OS) in newly diagnosed mCNPC patients (pts). AA has been previously coadministered with P (10 mg QD). As a lower dose of P (5 mg QD) was used in LATITUDE, we conducted additional safety analyses. Methods: 1199 pts with newly diagnosed, high-risk mCNPC (≥ 2 of 3 risk factors: Gleason ≥ 8, ≥ 3 bone lesions, visceral metastases) were randomized 1:1 to AA (1 gm QD) + P (5 mg QD) + ADT or placebos (PBOs) of AA and P + ADT: median treatment duration 24 and 14 mo, respectively. Safety analyses focused on key mineralocorticoid excess (ME)-related adverse events (AEs): hypertension (HTN) and hypokalemia. Results: Increased HTN with 5 mg/d P with AA + ADT (relative risk, 1.6 [95% CI, 1.4-1.9]) was similar to prior studies using 10 mg/d P (COU-AA-301: 1.4 [0.9-2.0]; COU-AA-302: 1.6 [1.2-2.1]). Of Gr 3/4 HTN events, 87% (109/126 [AA + P + ADT]) and 83% (52/63 [PBOs + ADT]) resolved to Gr ≤ 2. There were few cerebrovascular events: AA + P + ADT, 5; PBOs + ADT, 9. The protocol allowed increasing dose of P to 10 mg for ME-related AEs, but most Gr 3/4 HTN events were managed only by supplemental antihypertensives. Prior use of antihypertensives at study entry was predictive of Gr 3/4 HTN in both treatment arms (RR: 1.85; 95% CI, 1.14-3.01). Gr 3/4 hypokalemia increased with AA + P + ADT (10.4% [62/597]) vs PBOs + ADT (1.3% [8/602]); 89% (55/62) and 100% (8/8) of these events improved to Gr ≤ 2. Less than 1% of pts in either arm discontinued therapy for ME-related AEs. Conclusions: In-depth analysis of LATITUDE data confirms the safety of 5 mg/d P with AA + ADT and helps provide practical treatment guidance for managing mCNPC. Clinical trial information: NCT01715285. [Table: see text]
Multicenter prospective study of switching from GnRH agonists to GnRH antagonist for patients with early stage of castration resistant prostate cancer as a second-line hormonal therapy.
Authors: Yokomizo Yumiko , Hayashi Narihiko , Takizawa Akitoshi , Kobayashi Kazuki , Ohta Jun-ichi , Kitami Kazuo , Kishida Takeshi , Tsuchiya Futoshi , Yao Masahiro , Uemura Hiroji
Published: February 2018

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Background: It was reported that GnRH antagonist could extend progression free survival for prostate cancer patients significantly longer than GnRH agonist in a first line hormonal therapy. However, the usefulness of switching from GnRH agonist to GnRH antagonist as a second hormonal therapy remains obscure. We performed a multicentral prospective study to investigate whether the switching from GnRH agonist to GnRH antagonist (degalerix) for patients with castration resistant prostate cancer (CRPC) as the 2nd line hormonal therapy was effective. Methods: 37 patients who were pathologically diagnosed as prostatic adenocarcinoma and developed CRPC after 1st line hormonal therapy with GnRH agonist plus anti-androgens were enrolled. After confirming anti-androgen withdrawal syndrome, they were treated with switching from GnRH agonists to degalerix. The primary endpoint was PSA response (PSA decline or up to 10% over baseline PSA). Secondary endpoints were the time to 25% PSA increase from the baseline (PSA response time), PSA progression free survival (PPFS), the time to treatment failure, cancer specific survival, radiographic PFS (rPFS), and safety. Results: Mean age was 76 years old, super high risk; 20 cases (54.1%), high risk; 11 cases (29.7%), intermediate risk; 5 cases (13.5%), low risk; one case (2.7%). PSA responder rate was 24.3% (9 cases). In responders, the median PSA response time was 5.75 months, the median PPFS was 1.77 months, and rPFS rate at 3 months was 96%. Regarding safety, only 2 cases (5.4%) showed G3 of AE. The PSA response had no relationship with the change of serum testosterone, LH nor FSH. Conclusions: The effectiveness of switching from GnRH agonist to GnRH antagonist showed to be limited. Although no predictive factor of the switching was recognized, some long-term responders were seen. We expect the possibility of switching to GnRH antagonist for patients in the early stage of CRPC, especially non-metastatic status. Clinical trial information: UNKNOWN.
Expression of immune checkpoints on circulating tumor cells in men with metastatic prostate cancer (mPC).
Authors: Zhang Tian , Austin Rebecca Garland , Park Sally E , Runyambo Daniella , Boominathan Rengasamy , Rao Chandra , Bronson Elizabeth , Anand Monika , Healy Patrick , George Daniel J. , McNamara Megan Ann , Armstrong Andrew J.
Published: February 2018

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Background: Most immune checkpoint inhibitors have shown limited efficacy in unselected men with mPC, and there is limited understanding about which immune checkpoints (ICs) are relevant in mPC. We evaluated ICs on the cell surface of circulating tumor cells (CTCs) in patients with mPC. Methods: Patients were enrolled prospectively at the Duke Cancer Center in three cohorts: A) mCRPC starting the novel androgen receptor inhibitors abiraterone acetate (AA) or enza with or without sipuleucel-T, B) mCRPC with disease progression after AA or enza, and C) metastatic castration sensitive PC. The Cellsearch platform was used to capture EpCAM- and CK-expressing CTCs and analyzed for PD-L1, PD-L2, B7-H3, and CTLA-4 expression at baseline, 12 weeks, and at further disease progression. Results: Through August 2017, we enrolled 4 subjects in cohort A, 7 in cohort B, and 3 in cohort C. CTCs were detectable in every cohort. At baseline, B7-H3 was the most prevalent IC on a per-patient basis (mean 96% in cohort A, and 100% in cohort B, and 88% in cohort C). PD-L1 was detected less frequently (cohort A mean 8%, cohort B mean 42%, and cohort C mean 67%), with evidence of heterogeneity of CTC PD-L1 expression between and within patients. PD-L1 was expressed on 8% of CTCs in cohort C and cohort A, as compared to 28% of CTCs in cohort B, while CTLA-4 expression was not identified in cohort C, 3% of cohort A, and 15% of cohort B. B7H3 was expressed on 68% of cohort C, 91% of cohort A, and 98% of cohort B. PD-L2 was expressed on 0-7% of CTCs overall. Conclusions: Patients with mPC can have detectable and heterogeneous ICs on CTCs, particularly PD-L1 and B7-H3, and these characteristics can be monitored over time. B7-H3 was the most prevalent IC on CTCs, regardless of disease state. Our preliminary data suggests that men with mCRPC post-enza/AA have higher levels of PD-L1 and CTLA-4 expression on their CTCs as compared with men with mHSPC and mCRPC prior to enza/AA. Patient enrollment and analysis are ongoing.
Tumor fraction in circulating free DNA as a biomarker of disease dynamics in metastatic prostate cancer.
Authors: Choudhury Atish Dipankar , Werner Lillian , Ha Gavin , Freeman Samuel , Rhoades Justin , Reed Sarah , Gydush Greg , Rotem Denisse , Lo Christopher , Taplin Mary-Ellen , Harshman Lauren Christine , Zhang Zhenwei , O'Connor Edward P , Boehm Jesse , Getz Gad , Meyerson Matthew , Love J. Christopher , Hahn William C. , Adalsteinsson Viktor
Published: February 2018

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Background: Quantification of circulating free DNA (cfDNA) has been proposed both as a prognostic biomarker and as a biomarker of response and resistance to therapy. However, dynamics of cfDNA derived from both tumor and non-cancerous tissues through dense longitudinal monitoring over the course of treatment with multiple therapeutic modalities have not been well described. Methods: CfDNA isolated from banked and prospectively collected plasma samples from pts with metastatic castration-resistant prostate cancer (mCRPC) was subject to ultra-low pass (~0.1x coverage) whole genome sequencing (ULP-WGS). The fraction of cfDNA derived from tumor rather than non-cancerous tissues (i.e. the tumor fraction, or TFx) in each sample was estimated using a novel computational tool called ichorCNA, and was correlated with clinical features and response to therapy. Results: 663 plasma samples from 140 pts were included (median 3 samples/pt; range 1-20). TFx was correlated with the number of bone metastases (median TFx = 0.014 with no bone mets, 0.047 with 1-3, 0.190 for 4+), and with the presence of distant visceral mets (p < 0.0001). In multi-variate analysis, TFx was positively correlated with Alk Phos (p = 0.0227) and negatively correlated with Hgb (p < 0.001), but was not correlated with PSA (p = 0.75). All new treatment starts leading to > = 30% PSA decline at > = 6 weeks were associated with a decline in TFx from baseline when baseline TFx was > 7% (median TFx change -92.2%, range -70.3% to -100%); however, TFx in patients being subsequently maintained on secondary hormonal therapy without radiographic progression was quite dynamic. The total yield of cfDNA derived from both tumor and non-cancerous tissues tracked closely with TFx, and did not markedly change with initiation of therapies expected to lead to generalized tissue damage, such as chemotherapy and radiation, over the time scales examined. Conclusions: Decline in TFx is a promising biomarker for initial response to therapy, but subsequent temporary rises in TFx do not necessarily indicate the cessation of clinical benefit from secondary hormonal therapies. Analysis of cfDNA may allow a window into short-term tumor dynamics not easily assayed through other methods.
Hepatic effects assessed by review of safety data in enzalutamide castration-resistant prostate cancer (CRPC) trials.
Authors: Beer Tomasz M. , Chowdhury Simon , Saad Fred , Shore Neal D. , Higano Celestia S. , Iversen Peter , Fizazi Karim , Miller Kurt , Heidenreich Axel , Kim Choung Soo , Phung De , Barrus Jeffrey Kent , Nikolayeva Natalia , Krivoshik Andrew , Waksman Javier , Tombal Bertrand F.
Published: February 2018

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Background: Androgen receptor inhibitor enzalutamide (ENZA) improves survival in patients with metastatic CRPC. As the liver is the main route of ENZA elimination, this post hoc analysis evaluated the hepatic effects of ENZA versus comparators in controlled CRPC trials. Methods: Safety data from two large Phase 3, placebo (PBO)- (PREVAIL, NCT0121299; AFFIRM, NCT00974311) and two smaller Phase 2, bicalutamide (BIC)-controlled (STRIVE, NCT01664923; TERRAIN, NCT01288911) ENZA trials in men with CRPC were assessed for hepatic impairment-related adverse events (AEs) using the following standardized narrow MedDRA queries V19.1: hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; hepatitis, non-infectious; and liver-related investigation, signs, and symptoms. Liver-related laboratory test results were also evaluated. Data were summarized as follows: patients receiving ENZA in Phase 3 trials (n = 1671); patients receiving ENZA in Phase 2 trials (n = 380); patients receiving PBO (n = 1243); patients receiving BIC (n = 387); and combined ENZA-treated patients (n = 2051). Results: Percentages of hepatic impairment-related AEs ranged between 2.9% and 4.5% with ENZA, and were 2.7% with PBO and 5.4% with BIC (Table). The most common hepatic impairment-related AEs were increased aspartate (AST) and alanine aminotransferase (ALT; Table). Within each trial, the incidences of grade ≥3 AEs were similar, and dose reductions or discontinuations due to hepatic impairment-related AEs were low (Table). When adjusted for treatment exposure, AEs per 100 patient-years were lower with ENZA versus either PBO or BIC (Table). Conclusions: This combined analysis of CRPC trials demonstrates no hepatic safety signal with ENZA and thus routine liver tests are not required. Clinical trial information: NCT0121299; NCT00974311; NCT01664923; NCT01288911. [Table: see text]
Clinical experience with 100 consecutive patients treated with Lu-177-labeled PSMA-I&T radioligand therapy for metastatic castration-resistant prostate cancer.
Authors: Heck Matthias Michael , Schwaiger Sebastian , Knorr Karina , Retz Margitta , Maurer Tobias , Janssen Friederike , D´Alessandria Calogero , Wester Hans-Juergen , Gschwend Juergen E. , Schwaiger Markus , Tauber Robert , Eiber Matthias
Published: February 2018

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Background: To report our clinical experience with 177Lutetium-labeled prostate-specific membrane antigen-ligand (177Lu-PSMA-I&T) for systemic radioligand therapy in 100 consecutive patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: All patients were treated under a review board-approved compassionate use protocol. Eligibility criteria for 177Lu-PSMA-I&T therapy included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy or unsuitability for taxanes as well as positive 68Ga-PSMA tracer uptake of metastases in a prior PET-scan. Intravenous treatment with 177Lu-PSMA-I&T was given 6- to 8-weekly with an activity of 7.4GBq up to 6 cycles in patients without clinical or radiographic progression. We report prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS) and overall survival (OS) as well as toxicity. Results: Median age was 72 years (range 46-85) and median PSA level was 164 ng/ml (range 0-6178). Bone, lymph node and visceral metastases were present in 94%, 85% and 33% of patients, respectively. The median number of previous treatment regimens for mCRPC was 3 (range 1-6) and 84% of patients were pretreated with chemotherapy. At the time of evaluation, 286 cycles with 177Lu-PSMA-I&T were applied (median 2 cycles per patient, range 1-6), while treatment was still ongoing in 27% of patients. Overall, 4 and 6 cycles were applied in 33 and 15 patients, respectively. PSA decline ≥30%, ≥50% and ≥90% was achieved in 40%, 32% and 9% of patients, respectively. Median PSA-PFS was 3.4 months (95%CI 2.7-4.0), median cPFS was 4.1 months (95%CI 2.5-5.7) and median OS was 12.2 months (95%CI 8.8-15.7). Treatment-emergent hematologic grade 3/4 toxicities were anemia in 7%, thrombocytopenia in 5% and neutropenia in 4% of patients. Grade 3/4-non-hematologic toxicities were not observed. The main non-hematologic grade 1/2 toxicities were dry mouth in 18%, fatigue in 16% and loss of appetite in 9/% of patients. Conclusions: Radioligand therapy with 177Lu-PSMA I&T appears to be safe and active in late-stage mCRPC.
Occurrence of pathologic stage T3 disease at radical prostatectomy with isup grade group 1 (Gleason 3+3=6) prostate cancer.
Authors: Greenwald David Theodore , Wang Alice Y. , Huang Jason , Wadhwa Harpreet , Nimeh Tony , Cohen Justin J. , Yonover Paul
Published: February 2018

21

Background: Treatment of ISUP Grade Group 1 (Gleason 3+3 = 6) disease continues to evolve in the modern era. We examined our surgical database to investigate patterns of behavior in this pathologic subset. Methods: We reviewed the results of 1127 consecutive radical prostatectomies performed by our surgeons from 2012−2015 at various community and academic medical centers in Chicagoland. Specifically, we examined the ISUP Grade Group 1 (Gleason 3+3 = 6) patients in our database, 314 patients overall. Results: A review of our database revealed that of ISUP Grade Group 1 (Gleason 3+3 = 6) patients (n = 314), only 3.82% had pT3 disease (11 patients stage pT3a and 1 stage pT3b). The only patient of these 12 to have lymphovascular invasion (LVI) was the singular pT3b patient. Overall, ISUP Grade Group 1 (Gleason 3+3 = 6) pT3 disease represents only 1.06% of all prostatectomies in our database. Conclusions: In our large prostatectomy cohort, ISUP Grade Group 1 (Gleason 3+3 = 6) prostate cancer was rarely associated with extra−prostatic extension (pT3) or lymphovascular invasion (LVI), suggesting that it has very low metastatic potential. These findings give further support to the trend of increased utilization of active surveillance for low risk prostate cancer.
Mixed 20-peptide cancer vaccine in combination with docetaxel and dexamethasone for castration-resistant prostate cancer: A randomized, double-blind, placebo-controlled, phase 2 trial.
Authors: Noguchi Masanori , Arai Gaku , Egawa Shin , Ohyama Chikara , Naito Seiji , Matsumoto Kazumasa , Uemura Hirotsugu , Nakagawa Masayuki , Nasu Yasutomo , Eto Masatoshi , Suekane Shigetaka , Sasada Tetsuro , Shichijo Shigeki , Yamada Akira , Kakuma Tatsuyuki , Itoh Kyogo
Published: February 2018

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Background: A novel cancer vaccine consisting of 20 mixed peptides (KRM-20) was designed to induce cytotoxic T lymphocytes (CTL) against twelve different tumor-associated antigens. The aim of this phase 2 trial was to examine whether KRM-20 in combination with docetaxel and dexamethasone enhances anti-tumor effects in patients with castration-resistant prostate cancer (CRPC). Methods: In this double-blind, placebo-controlled, randomized, phase 2 study, we enrolled chemotherapy-naïve patients with progressive CRPC from 10 medical centers in Japan. Eligible patients were randomly assigned 1:1 centrally to either KRM-20 combined with docetaxel and dexamethasone or placebo with docetaxel and dexamethasone. Patients initially received 5 weekly subcutaneous KRM-20 (20 mg) or placebo injections with daily oral dexamethasone (1 mg) following 5 courses of docetaxel (70 mg/m2 every 3 weeks). The primary endpoint was to compare each treatment for prostate-specific antigen (PSA) decline. Results: Between Jul 31, 2013 and Jul 11, 2014, 51 patients were enrolled to the trial: 25 were assigned to the KRM-20 arm, and 26 were allocated to the placebo arm. Mean % PSA levels from baseline in the KRM-20 arm significantly decreased during the treatment compared witht those in the placebo arm ( P = 0.028, MANOVA). Human leukocyte antigen matched peptide-specific immunoglobulin G ( P = 0.018) and CTL ( P = 0.007) responses in the KRM-20 arm significantly increased after the treatment. The appearance of myeloid-derived suppressor cells in the KRM-20 arm significantly decreased after the treatment ( P = 0.007). The addition of KRM-20 did not result in increased toxicity. There was no between-group differences in progression-free or overall survival. Conclusions: These findings suggest potential clinical benefits for the combined use of KRM-20 with docetaxel and dexamethasone in patients with CRPC. Clinical trial information: UMIN000011028.
Cabozantinib for metastatic castration-resistant prostate cancer (mCRPC) following docetaxel: Combined analysis of two phase III trials.
Authors: Pond Gregory Russell , Sonpavde Guru , Fizazi Karim , De Bono Johann S. , Basch Ethan M , Scher Howard I. , Smith Matthew Raymond
Published: February 2018

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Background: Two phase III trials, COMET-1 and COMET-2, have reported that cabozantinib did not extend overall survival (OS) outcomes compared to prednisone and prednisone plus mitoxantrone respectively, in unselected post-docetaxel patients with mCRPC. We conducted a retrospective analysis of a combined dataset of these trials in an attempt to identify a benefit in subsets of patients based on prognostic risk factors. Methods: Baseline characteristics and survival data were combined for COMET-1 and COMET-2. Prognostic ability of baseline factors on survival was evaluated using Cox proportional hazards regression models, which incorporated the factors in the modern post-docetaxel nomogram and overall bone scan lesion area (BSLA) by computer-assisted analysis. Regression models included trial as a stratification factor. Evaluation of potentially benefited subsets was performed by the use of interaction terms between the factors and cabozantinib. The hazard ratio between cabozantinib and comparator arms was evaluated after adjusting for baseline prognostic factors. All tests were 2-sided and a p-value ≤0.05 was considered statistically significant. Results: A total of 1147 post-docetaxel patients with mCRPC were available (1028 from COMET-1 and 119 from COMET-2). Age, albumin, LDH and BSLA were statistically significant prognostic factors in addition to variables from the Halabi model (site of metastases, pain, docetaxel-free interval, ECOG-PS, hemoglobin, alkaline phosphatase, PSA). There was no consistent interaction effect on survival between cabozantinib vs. comparator arms for any prognostic group. After adjusting for multiple potential prognostic factors, treatment with cabozantinib vs. comparator was associated with an observed hazard ratio of 0.77 (95% CI = 0.65 to 0.92, p = 0.003) for survival. Conclusions: After combining data from both COMET-1 and COMET-2 trials, no differential effect of cabozantinib on survival was observed for any prognostic risk factor. A modest treatment effect of cabozantinib on OS was observed after controlling for multiple potential prognostic factors.
Effect of HER3 dimer feedback upregulation via PI3K-AKT-mTOR pathway inhibition on androgen receptor (AR) stabilization in metastatic prostate cancer.
Authors: Galazi Myria , Salji Mark , Weitsman Gregory , Gomez Valentin , Leung Hing , Ng Tony
Published: February 2018

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Background: Metastatic castration resistant prostate cancer (CRPC) is dependent on persistent activation of the AR. In addition, the AR and PI3K-AKT-mTOR pathways have been shown to regulate each other through complex feedback mechanisms. Various early phase clinical studies are currently investigating the role of PI3K-AKT-mTOR pathway inhibitors in improving outcomes in metastatic CRPC. We hypothesise that the formation of a HER3 (human epidermal growth factor receptor) heterodimer, has an important role in regulating the AR and PI3K-AKT-mTOR feedback loop and that its detection can predict response to PI3K-AKT-mTOR pathway inhibition. Methods: LNCAP cells were stably lentiviral transduced with shRNA against HER3. The effect of PI3K-AKT-mTOR inhibition by DS7423, GDC0068, GDC0941 and Everolimus on AR and its direct target gene PSA was evaluated by western blot and real-time quantitative PCR. CWR22 and 22RVI mouse xenograft tumours were stained with fluorescently labelled antibodies for fluorescence lifetime imaging microscopy (FLIM) to assess HER2-HER3 dimerisation by FRET (fluorescence resonance energy transfer) using TRI2 software. Results: We show that there is a statistically significant increase in AR protein levels and PSA gene expression in LNCAP NTC vs HER3kd cells upon treatment with the dual PI3K-mTOR inhibitor DS7423. In addition, there is decreased inhibition of AKT phosphorylation in LNCAP NTC cells, whereas in the absence of HER3 there is complete abrogation of pAKT levels. The use of GDC0941 and Everolimus resulted in similar effect on AR in the LNCAP NTC vs HER3kd cells, however this is less prominent. The AKT inhibitor, GDC0068, has little effect on AR in the presence or absence of HER3. FLIM demonstrated increase in FRET as evidence of HER3 heterodimerisation in 22RVI compared to CWR22 xenograft tissue, showing that HER3 dimerisation emerges in metastatic prostate cancer that has progressed to a castrate resistant phenotype. Conclusions: Our results suggest that HER3 stabilises the AR upon PI3K-AKT- mTOR pathway inhibition and that detection of a HER3 heterodimer can be used as a predictive biomarker of response to these therapies.
Impact of enzalutamide (ENZA) vs. bicalutamide (BIC) on health-related quality of life (HRQoL) of patients (pts) with castration-resistant prostate cancer (CRPC): STRIVE study.
Authors: Concepcion Raoul , Armstrong Andrew J. , Karsh Lawrence Ivan , Holmstrom Stefan , Ivanescu Cristina , Dunshee Curtis , Agarwal Neeraj , O'Kelly Michael , Naidoo Shevani , Olsson Carl A. , Phung De , Ratitch Bohdana , Wang Fong , Kral Pavol , Penson David F.
Published: February 2018

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Background: In STRIVE pts with CRPC (M0 n = 139; M1 n = 257), median time to 10-point decrease from baseline in FACT-P total for ENZA vs. BIC was 8.4 vs. 8.3 months (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.70, 1.19; p = 0.49). That assumed missing data was missing at random (MAR) and censored pts with no deterioration in FACT-P at last assessment. As HRQoL may worsen after progression/adverse events, for all STRIVE pts we replaced the MAR assumption with assumptions more likely to reflect clinically plausible HRQoL decline. Methods: Analyses of HRQoL decline (minimum clinically important difference or higher decrease in FACT-P vs. baseline) used a missing not at random (MNAR) assumption using a pattern mixture model (PMM) via sequential modeling with multiple imputation when imputation varies by reason of treatment discontinuation. Analysis of time to first clinically meaningful deterioration vs. baseline used a piecewise exponential survival multiple imputation model with reason-specific ∆ adjustment patterns similar to PMM analysis. Results: PMM analysis showed differences at week 61 in mean HRQoL change from baseline favoring ENZA vs. BIC for 7 of 10 scores: physical (PWB), functional, emotional (EWB), and social (SWB) well-being; FACT-P trial outcome index; FACT-G total; FACT-P total (all clinically meaningful except PWB). In the piecewise exponential survival imputation model, ENZA had a significantly lower risk of first deterioration in FACT-P total (0.76 [0.60, 0.95]), FACT-G total (0.66 [0.52, 0.83]), Prostate Cancer Subscale (PCS) pain-related (0.78 [0.62, 0.97]), SWB (0.49 [0.38, 0.64]), and EWB (0.58 [0.45, 0.75]) vs. BIC. For remaining domain scores, ENZA reduces risk of first deterioration (HR < 1) but the 95% CI includes 1 (which means not significant); sensitivity analysis showed similar results. Conclusions: In STRIVE pts, declines in all FACT-P scores were smaller for ENZA vs. BIC up to week 61. Comparison of change from baseline at week 61 favored ENZA for 7 of 10 scores (6 clinically meaningful). ENZA had a significantly lower risk of first deterioration in FACT-P or FACT-G total, PCS pain-related, EWB, and SWB. Clinical trial information: NCT01664923.
Outcomes in patients (Pts) with advanced prostate cancer and inactivating germline mutations in BRCA2 or ATM.
Authors: Yip Steven , Khalaf Daniel , Struss Werner J. , Sunderland Katherine , Vandekerkhove Gillian , Warner Evan W , Annala Matti , Wyatt Alexander William , Chi Kim N.
Published: February 2018

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Background: Germline mutations in homologous recombination repair (HRR) genes, including BRCA2, are present in 6-12% of pts with metastatic castration-resistant prostate cancer (mCRPC). BRCA2 germline mutations are associated with high-grade and poor-prognosis localized disease, while outcomes in pts with advanced prostate cancer continue to be defined. Methods: Germline DNA from 536 consecutive mCRPC pts in our liquid biopsy program were screened for BRCA2 and ATM gene mutations using targeted sequencing. Kaplan-Meier curves were used to estimate the median time from androgen deprivation therapy (ADT) initiation to mCRPC, progression free survival (PFS) on first-line androgen receptor (AR) targeted therapy, and overall survival (OS). Outcomes in BRCA2 or ATM germline mutation carriers and a subset of the total sample of HRR wild-type (WT) pts, who had clinical data available (n = 113), were compared using the log-rank test. Results: 26/536 (4.9%) of pts had germline BRCA2 (n = 22) or ATM mutations (n = 4). After ADT initiation, HRR mutated pts progressed to mCRPC with a median time of 13.4 mo compared to 19.0 mo in WT pts (HR = 1.6, [95% CI 1.0-2.5], p = 0.03). HRR mutated pts had a median PFS on first-line AR-targeted therapy in the mCRPC setting of 3.3 mo versus 7.9 mo in WT pts (HR = 2.2, [95% CI 1.3-3.5], p = 0.002). OS for HRR mutated pts from the time of ADT was 57.7 mo in contrast to 104.9 mo in WT pts (HR = 1.8, [95% CI 1.0-3.4], p = 0.07). OS from time of CRPC was 29.7 mo in HRR mutated pts versus 50.3 mo in WT pts (1.6, [95% CI 0.8-2.9], p = 0.16). Conclusions: Germline HRR mutated pts perform poorly with shorter PFS on first-line AR-targeted therapy and time to mCRPC, in contrast to WT pts. These findings support the hypothesis that BRCA2 and ATM gene mutated pts have poor outcomes with current AR-targeted treatments and should be evaluated for alternate regimens.
Prostate cancer presentation, treatment selection, and outcomes among men with HIV/AIDS: A clinical, stage, and age-matched analysis.
Authors: Ruden Maria , Olivares Christopher , Fakhoury Mathew Q , Vidal Patricia Q , Hollowell Courtney MP , Psutka Sarah P
Published: February 2018

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Background: The clinical presentation, oncologic outcomes and the optimal management of prostate cancer (PC) among human immunodeficiency virus-seropositive (HIV+) men are poorly described. Our objective was to compare the clinical characteristics, treatment decisions and oncologic outcomes in a contemporary series of HIV+ and HIV negative (HIV-) men with PC. Methods: Clinical data for 3135 men treated for PC at Cook County Hospital (2000-16) were reviewed. HIV+ patients (N = 46) were matched 1:2-3 by age and clinical stage to HIV-negative controls (N = 137). Clinicopathologic features, primary treatment, and oncologic outcomes were compared with Kaplan Meier and Cox proportional hazards analyses. Results: HIV- and HIV+ patients were similar with respect to median age (58.2 vs. 57.2 years, p = 0.2), initial PSA (10.6 vs. 10.5 ng/mL, p = 1), clinical stage (94% cT1/2 vs. 88%, p = 0.4), 8% cN1 vs. 6.5%, p = 1; 10.9% cM1 vs. 10.9%, p = 1), ECOG performance status (0-1 in 99% vs. 100%, p = 1). Among HIV+ men, 67.4% had a history of AIDS, and 91.3% were on HAART at diagnosis with median viral load and CD4+ count of 40 copies/mL and 400 cells/mm3. Median time from HIV diagnosis to PC diagnosis was 8.6 years. Among men with localized disease (N = 153), HIV+ men (N = 37) were more likely to receive radiation therapy (59.5% vs. 44.8%) or no therapy at all (13.5% vs. 4.3%) and less likely to receive surgery (16.2% vs. 30.2%), or to initiate active surveillance (10.8% vs. 16.4%; p = 0.04 overall) than HIV-. There were no differences in rates of biochemical recurrence (Hazard ratio [HR] 0.79; p = 0.6), clinical progression (HR 0.89, p = 0.8), castration resistance (HR 0.71, p = 0.1), or PC-death (HR 3, p = 0.1). However, HIV+ status was associated with an increased risk of all-cause death (HR 2.89, p = 0.04) with median follow-up of 4.2 years (range 0-14). Conclusions: Matched by age and stage, HIV+ men with localized PC were observed to receive surgery and definitive treatment overall at significantly lower rates than HIV- controls. Oncologic outcomes were similar between HIV+ and HIV- men. Further research is necessary to define optimal PC treatment selection in men with HIV.
Outcomes of metastatic castration resistant prostate cancer (mCRPC) patients with DNA repair germline mutations (gDDR) following first taxane-based treatment.
Authors: Puente Javier , Romero-Laorden Nuria , Vallespin Garcia Elena , Piulats Josep M. , Saez M Isabel , Fernandez Parra Eva , Perez Valderrama Begona , Borrega Pablo , Cendon Ylenia , Ibáñez Kristina , Lainez Nuria , Heras Lucia , Velez Edelmira , Almagro Elena , Zambrana Francisco , García Domínguez Rocío , Contreras Jose Antonio , Lapunzina Pablo , Olmos David , Castro Elena
Published: February 2018

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Background: Germline DDR have been identified in up to 12% of mCRPC patients. Initial results from various retrospective series have reported discordant impact in clinical outcomes associated to these gDDR following conventional treatments. PROREPAIR-B (Castro et al ESMO 2017) is the first prospective study to address this question. In this planned sub-analysis, we report mCRPC treatment outcomes associated to taxanes. Methods: PROREPAIR-B (NCT03075735) is a prospective multicentre observational cohort study. Patients diagnosed with mCRPC, with unknown mutational status at study entry and who were going to start a first-line treatment for mCRPC were eligible. For this sub-analysis patients who received docetaxel or cabazitaxel as first-taxane were selected. The endpoints of this sub-analysis included to assess the impact of BRCA1, BRCA2, ATM and PALB2 and other gDDR on cause-specific survival (CSS), progression free survival (PFS), time to PSA progression (bPFS) and response to the first administered taxane as 1st or 2nd line therapy. Results: 326 (12 BRCA2, 8 ATM and 1 BRCA1 mutation carrier [gMUT]) out of 419 patients were eligible for this analysis. Diagnostic characteristic included Stage IV 51%, G8-10 60%. At the time of taxane initiation median PSA was 30.1 ng/mL, 84%, 48% and 11% of patients had bone, nodal and visceral metastases. CSS from first-taxane were not significantly different between gMUT and non-carriers (NC) (16.9 vs 23.2 m, p > 0.05). However, in BRCA2 carriers was significantly shorter than in NC (13.1 vs 23.3 m, p = 0.026). Despite a trend to higher PSA response rates in gMUT compared to NC (n = 288, 63% vs 42%, p = 0.07, BRCA2 55%, p > 0.05), PFS were not significantly different between both groups (7.2 vs 7.8 m, p > 0.05), with a trend to shorter survival in BRCA2 carriers (4.5 vs 7.4 m, P = 0.11). Conclusions: These results suggest that DDR mutation carriers respond to taxanes with similar time to progression compared to NC, with the exception of BRCA2 carriers, who despite to the initial response to taxanes, presented worse survival outcomes. This highlights the need for close monitoring and novel therapies in this population. Clinical trial information: NCT03075735.
Molecular profiling of liquid biopsies from patients (pts) with bone metastatic castration-resistant prostate cancer (BM-CRPC) treated with radium-223 (RA-223) to reveal differential enrichment for markers that correlate with overall survival (OS).
Authors: Corn Paul Gettys , Subudhi Sumit Kumar , Araujo John C. , Vardaki Ioulia , Aparicio Ana , Tu Shi-Ming , Pagliaro Lance C. , Zurita Amado J. , Logothetis Christopher , Panaretakis Theocharis
Published: February 2018

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Introduction: RA-223 prolongs OS in BM-CRPC pts but predictive markers are lacking. We hypothesized that molecular profiling of plasma-derived extracellular vesicles (EVs) from BM-CRPC pts treated with RA-223 would predict efficacy and inform development of combinations. Methods: Paired baseline (BL) and end of treatment (EoT) blood samples were collected from 25 pts treated with RA-223. Pts were stratified by median OS into 3 groups: 1) 6.3 months (range 3.3-8.5, n=5 pts, UnFav OS), 2) 18.2 months (range 12.6-19.4, n=7 pts, Middle OS) and 3) 27.6 months (range 23.1-33.8, n=13 pts, Fav OS). EVs were isolated from plasma and analyzed for specific proteins and RNA transcripts. Marker profiles by domain and analytic method were determined in pts from the stratified OS groups. Results: At EoT, there is enrichment of RNA transcripts and proteins involved in regulating immune responses, DNA Damage Response (DDR) and bone metabolism (Table). By benchmarking molecular signatures in pts with UnFav Os and Fav OS, we could analyze the molecular profiles of pts in the Middle OS group and stratify them to UnFav OS or Fav OS groups. Conclusion: Plasma-based molecular markers are predictive for RA-223 efficacy. An association between OS and immune and DDR profiles in men with BM-CRPC may indicate mechanism of action and identify subsets most likely to benefit. These preliminary results provide rationale for combination therapy with RA-223 and immune-checkpoint blockade or PARP inhibition. Clinical trial information: NCT02135484. [Table: see text]
Oncological and postoperative outcome of salvage PSMA-radioguided surgery in recurrent prostate cancer.
Authors: Horn Thomas , Rauscher Isabel , Eiber Matthias , Wester Hans-Juergen , Schottelius Margret , Heck Matthias Michael , Gschwend Juergen E. , Maurer Tobias
Published: February 2018

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Background: Positron-emission tomography (PET) directed against PSMA allows detection of even small metastatic prostate cancer (PC) lesions at low PSA values. In a subset of patients (pts) with recurrent PC salvage surgery might be beneficial. To facilitate removal during salvage surgery, we recently introduced PSMA-targeted radioguided surgery (PSMA-RGS). Methods: 121 consecutive patients with recurrent PC (PSA median: 1.13 ng/ml, range: 0.00 – 13.90 ng/ml; 9 pts under androgen-deprivation therapy) and soft-tissue lesions on 68Ga-PSMA PET after radical prostatectomy underwent 111In- or 99mTc-based PSMA-RGS between April 2014 and May 2017. The rate of complete biochemical response (cBR; PSA < 0.2ng/ml) was determined 6-16 weeks following PSMA-RGS. Biochemical recurrence-free survival (bRFS), PC-specific treatment-free survival and postoperative complications were evaluated. Results: Metastatic soft-tissue lesions from PC metastases could be removed in 120/121 pts (99.2%). One patient died six days postoperatively from a pulmonary embolism, five patients were lost to follow-up. Eleven pts suffered from Clavien grade III complications within 90d from surgery. In 75 out of 115 (65.2%) pts cBR was achieved. cBR was more likely in patients with a preoperative PSA level < 1.13 (76.3% vs. 52.7%) or a single anatomical location of recurrence (71.9% vs. 58.8%). Median bRFS was 5.1 months. At the time of analysis, 15 pts exhibited an ongoing cBR for at least 12 months (range: 12-32 months). A significantly longer bRFS was achieved in pts with a preoperative PSA < 1.13 ng/ml (median 14.9 vs 3.2 months, p = 0.02). In pts with a single compared to multiple location of recurrence we observed a trend towards a longer median bRFS (8.2 months vs. 3.5 months, p = 0.08). After one year of follow-up, 61.6 % of pts did not receive any further PC-directed treatment. Conclusions: PSMA-RGS is a promising tool to enhance intraoperative detection of metastatic lesions in PC with an acceptable complication rate. It leads to a high number of biochemical response with substantial duration in a subset of pts. Our data showed that bRFS was highest in patients with a low preoperative PSA and a single anatomical site of recurrence.
Serum neuroendocrine (NE) markers and clinical characteristics of treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) in men with metastatic castration resistant prostate cancer (mCRPC): Data from the West Coast Prostate Cancer Dream Team.
Authors: Aggarwal Rahul Raj , Zhang Li , Beer Tomasz M. , Youngren Jack , Stromlund Alise , Bell Alexander , Foye Adam , Playdle Denise , Alumkal Joshi J. , Reiter Robert Evan , Gleave Martin , Evans Christopher P. , Thomas George V. , Huang Jiaoti , True Lawrence D. , Rettig Matthew , Lara Primo , Chi Kim N. , Small Eric Jay
Published: February 2018

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Background: Detection of t-SCNC in mCRPC patients relies primarily on histopathologic evaluation (Histo) of a metastatic tumor biopsy (bx), likely leading to underdiagnosis. The clinical features of t-SCNC and the diagnostic utility of serum NE markers (neuron-specific enolase (NSE) and chromogranin (CGA)) were evaluated. Methods: Eligible patients (pts) underwent a metastatic bx at one of 5 centers. Histo was performed by 3 independent pathologists (JH, GT, LT). NE markers were evaluated in a central lab (lower limit = 1 ng/mL). Kruskal-Wallis and chi-square test were used to compare continuous and categorical variables, respectively. Receiver-operative-curve (ROC) analysis of serum NE markers was undertaken. Results: 160 consecutive pts with available Histo and NE markers were included. t-SCNC was found in 27 pts (17%). Detection of t-SCNC was observed in all bx sites, including liver (14%), lymph node (19%) and bone (14%). Clinical features are shown in the Table. By ROC analysis, if both serum NSE was > 6.05 ng/mL and chromogranin was > 3.1 ng/mL, the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for the detection of t-SCNC were 95%, 50%, 98%, and 22%, respectively. Conclusions: Many of the classic features of de novo SCNC, including low PSA levels, do not reliably distinguish t-SCNC. In contrast, serum NE markers have diagnostic utility with high sensitivity and NPV, but low specificity and PPV. Heterogeneous NE differentiation may partially account for these findings. Clinical trial information: NCT02432001. [Table: see text]
Real-world experience with docetaxel for castration-sensitive prostate cancer from a population-based analysis.
Authors: Lavoie Jean-Michel , Zou Kevin , Khalaf Daniel , Eigl Bernhard J. , Kollmannsberger Christian K. , Vergidis Joanna , Noonan Krista , Zulfiqar Muhammad , Finch Daygen L. , Chi Kim N.
Published: February 2018

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Background: Phase III clinical trials have demonstrated efficacy with an overall survival (OS) benefit for the addition of docetaxel (DOC) to androgen deprivation therapy (ADT) for the treatment of metastatic castration-sensitive prostate cancer (mCSPC). The clinical effectiveness of DOC with ADT in the general patient population remains undefined. Methods: A population-based retrospective review was conducted of patients (pts) with mCSPC who received DOC at the BC Cancer Agency from 04/2015 to 02/2017. Patient and disease characteristics were extracted. Safety and clinical-effectiveness were evaluated. Results: 183 records were identified; 156 pts received DOC in the mCSPC setting. Baseline characteristics included a median age of 67 years (range 44-86) and visceral metastases (mets) present in 18%; 80% had high volume disease with 74% having > 3, and 54% > 10 bone mets; 76% had de-novo metastatic disease. All 6 planned DOC cycles were delivered in 126 cases (81%); it was stopped early for: toxicity in 15 (10%), unrelated death in 1 (0.6%), pt preference in 5 (3%) or disease progression in 9 (6%) cases. Dose reductions and delays were required in 61 (39%) and 25 (16%) cases, respectively. Grade 3-5 adverse events were noted in 62 (40%) cases, with 28 (18%) cases of febrile neutropenia (FN); there were no treatment-related deaths. Pts with FN had more bone mets (p = 0.046), but there was no difference in time from start of ADT to initiation of docetaxel, age, baseline performance status, PSA, or visceral involvement. PSA ≤ 0.2 ng/L was achieved in 41 (28%) cases after 6 months of ADT and maintained in 13 (8%) cases after 12 months. 41% of pts had developed CRPC within 1-yr, with a median time to CRPC of 14.3 months. Treatment for CRPC was given in 54 cases, with most pts receiving either abiraterone or enzalutamide (87%) with a PSA decline ≥50% occurring in 47%. Conclusions: Effectiveness of DOC with ADT in a general population of pts with mCSPC was associated with poorer outcomes and high rates of toxicity compared to the phase III studies. Response rates to first-line treatment for mCRPC with abiraterone or enzalutamide appear similar to those previously reported.