bluuebunny/crossref_metadata_2025 huggingface dataset:
Everolimus plus bicalutamide for castration resistant prostate cancer (CRPC): Bench to bedside and back.
Authors: Chow Helen , Ghosh Paramita , D'Abronzo, Leandro S , de Vere White Ralph , Dall'Era Marc , Evans Christopher P. , Yap Stanley A , Lara Primo , Pan Chong-Xian
Published: February 2017

189

Background: We previously reported that the mammalian target of rapamycin (mTOR) pathway was upregulated in CRPC, and that simultaneous blockade of both androgen receptor (AR) and mTOR pathways synergized in killing CRPC cells. Methods: Eligible patients (pts) must have progressive CRPC with serum testosterone <50 ng/dl. No prior bicalutamide (except to prevent flare) or everolimus was allowed. Treatment regimen included daily bicalutamide 50 mg and everolimus 10 mg orally. Primary endpoint was prostate specific antigen (PSA) response (defined as ≥30% reduction). Sample size of 23 pts would have the power of 0.8 and alpha error of 0.05 (one-sided) if the combination had a PSA response rate of 50% vs. a historical rate of 25% with bicalutamide alone. Molecular correlative studies including serum ERBB3 levels were performed by ELISA. LNCaP and C4-2 cells, modeling bicalutamide-sensitivity and resistance, respectively, were transfected with ErbB3 or an empty vector and subjected to western blotting. Results: Of 24 pts enrolled, the mean number of treatment cycles was 7.9 (1.0-23.0). Eighteen pts had a PSA response (75%, 95% CI: 0.53-0.90). Median overall survival was 28 months (95% CI 14.1-42.7). Fourteen pts (54%, 95% CI 0.37, 0.78) developed Grade 3 (13 pts) or Grade 4 (1 pt with sepsis) adverse events attributed to study treatment. Pts with partial response showed a greater decline in ErbB3 (P=0.037) compared to those with stable disease or disease progression. Consistent with these findings, everolimus induced a decline in ErbB3 in hormone-sensitive LNCaP cells but failed to affect ErbB3 in CRPC C4-2 cells, which expressed 8-fold higher levels of ErbB3. Increased expression of ErbB3 in LNCaP cells resulted in resistance to everolimus, whereas bicalutamide initially prevented this effect. Prolonged exposure to bicalutamide also resulted in an increase in ErbB3 which correlated with increased growth rates and cell invasion. Conclusions: The combination of bicalutamide and everolimus has very encouraging efficacy in men with bicalutamide-naïve CRPC, but with substantial everolimus-related toxicity. ERBB3 may contribute to resistance and deserves further study. Clinical trial information: NCT00814788.
Adjuvant radiotherapy versus wait-and-see strategy for pathologic T3 or margin-positive prostate cancer: A meta-analysis.
Authors: Shaikh Mohammad Parvez , Harkenrider Matthew M. , Wu Meng-Jia
Published: February 2017

19

Background: Optimal management after radical prostatectomy (RP) remains controversial in patients with pathologic T3 or margin-positive prostate cancer with the options being early adjuvant radiotherapy (ART) versus wait-and-see (WS). Methods: A comprehensive Medline search to identify randomized controlled trial (RCT) of ART vs WS was done. Synthesized results from the included studies show Metastasis-Free Survival (MFS) and overall survival (OS) rates at 10 years as well as Grade 2 or greater GI and GU toxicities in the studies. Results were based on the random-effect (RE) model if there was evidence of between-trial heterogeneity, otherwise the fixed-effect (FE) model was used. Results: A total of 3 RCTs (ARO9602/AUO AP09/95, EORTC22911, SWOG8794) were identified with 1,737 patients (ART: n=864, WS: n=873). 10-year estimates of MFS and OS rates were reported for SWOG and EORTC studies, and estimated for ARO 96-02/AUO AP09/95 study from their Kaplan-Meier curves (Table). Pooled 10-year MFS data showed a significant improvement with ART vs WS (OR= 0.77; 95% CI 0.62–0.96, p=0.02, FE). However, pooled 10-year OS was not significantly different (OR= 0.98; 95% CI 0.64–1.49, p=0.91, RE). Grade 2 or greater GI toxicity was reported by all three studies and was significantly higher in ART (2.5%) compared with WS (1.1%), p=0.04. Grade 2 or greater GU toxicity was reported by ARO9602 and EORTC studies and was significantly higher in ART (17.1%) compared with WS (10.3%), p=0.0004. Conclusions: 10-year MFS is significantly improved with ART compared with WS. No benefit in 10-year OS was found. Grade 2 or greater GI and GU toxicities where greater in ART compared with WS. [Table: see text]
3-year safety follow-up of radium-223 dichloride (Ra-223) in patients (Pts) with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases (Mets) from ALSYMPCA.
Authors: Parker Chris , Vogelzang Nicholas J. , Sartor A. Oliver , Coleman Robert E. , Fang Fang , Skjorestad Irene , Nilsson Sten
Published: February 2017

195

Background: In ALSYMPCA, the first-in-class α-emitter Ra-223 had a highly favorable safety profile and was well tolerated. Safety monitoring of Ra-223 is essential for a complete safety profile. Here are final safety data including long-term follow-up safety 3 years after last pt’s first injection (inj). Methods: Pts received 6 inj and entered designated follow-up from 4 wks after their last inj to 3 years after first inj. Pts were to be evaluated during tx period and 9 follow-up visits. All adverse events (AEs) were collected until 12 wks after last inj; thereafter, only AEs deemed tx-related were collected. Additional long-term safety data were assessed by specific diseases including acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and new primary cancer in bone or other organs. Results: Safety population (pts receiving ≥ 1 inj) included 901 pts (Ra-223, n = 600; placebo [pbo], n = 301); 572 pts (Ra-223, n = 405; pbo, n = 167) entered follow-up. 60 pts (Ra-223, n = 49; pbo, n = 11) completed all follow-up visits. Overall, 564 (94%) Ra-223 and 292 (97%) pbo pts had ≥ 1 tx-emergent AE (Table). During long-term follow-up, there were no reports of AML, MDS, or new primary bone cancer. New primary cancers in other organs were reported: 2 Ra-223 (1 bladder, 1 lymph node mets), 3 pbo (2 skin, 1 adenocarcinoma rectum and sigmoideum), and 2 pbo cross-over pts (1 skin, 1 meningioma). Aplastic anemia was reported in 1 Ra-223 pt. Conclusions: Ra-223 remained safe and well tolerated 3 years after the last pt’s first inj. No major safety issues were identified during the ALSYMPCA 3-year long-term follow-up. Clinical trial information: NCT00699751. [Table: see text]
Androgen deprivation with or without radiation therapy for clinically node-positive prostate cancer.
Authors: Efstathiou Jason Alexander , Lin Chun Chieh , Gray Phillip John , Jemal Ahmedin
Published: February 2017

198

Background: Clinically lymph node positive (cN+) prostate cancer (PCa) is an often fatal disease. Its optimal management remains largely undefined given a lack of prospective, randomized data to inform practice. We sought to describe modern practice patterns in the management of cN+ PCa and assess the effect of adding radiation therapy (RT) to androgen deprivation therapy (ADT) on survival using the National Cancer Data Base. Methods: Patients with cN+ PCa with no distant metastases diagnosed between 2004-2011 were included. Five-year overall survival for patients diagnosed between 2004-2006 and treated with ADT alone or ADT+RT were compared. Propensity score (PS) matching was used to balance baseline characteristics and Cox multivariate regression analysis was used to estimate hazard ratios (HRs) for all-cause mortality. Results: 3,540 patients were included. 32.2% were treated with ADT alone and 51.4% received ADT+RT. Patients aged <65, those with private insurance, lower comorbidity scores, higher Gleason scores, and lower PSA values were significantly more likely to receive ADT+RT (p<.05). After PS matching, 318 patients remained in each group. Compared to ADT alone, ADT+RT was associated with a 50% decreased risk of five-year mortality (HR: 0.497, 95% CI: 0.37-0.67, p<.001). Conclusions: Using data recorded in a large national database, we have identified a significant survival benefit for patients with cN+ PCa treated with ADT+RT. These data, if appropriately validated, suggest that a significant proportion of such patients at high risk for prostate cancer death may be undertreated warranting a re-evaluation of current practice guidelines.
Prognostic significance of the PSA nadir after salvage radiotherapy following radical prostatectomy in prostate cancer.
Authors: Wiegel Thomas , Bartkowiak Detlef , Bottke Dirk , Siegmann Alessandra , Budach Volker , Hinkelbein Wolfgang
Published: February 2017

207

Background: Salvage radiotherapy (SRT) is a curative approach in recurrent prostate cancer after radical prostatectomy. The outcome depends on various parameters. We report the long term results of SRT with special respect to the course of PSA after SRT. Methods: Between 1997 and 2007, 307 patients received SRT with 66.6 (N=240) or 70.2 Gy (N=67) using CT-based 3D planning. The median pre-SRT PSA was 0.297 ng/ml. Post-SRT progression was defined as either PSA rising >0.2 ng/ml above nadir, or hormone treatment, or clinical recurrence. Data were analyzed with the Kaplan-Meier method (Logrank-test) and with multivariate Cox regression. Results: Patients were followed up for median 7.2 (max. 14.4) years. Recurrence occurred in median 9.4 months post-RP. In 112 patients, SRT was administered before their PSA reached 0.2 ng/ml, 195 men were above that threshold. After SRT, 222 patients achieved a PSA nadir <0.1 ng/ml, 85 retained higher values. SRT given at a PSA <0.2 ng/ml correlated with achieving a post-SRT nadir <0.1 ng/ml (p<0.0001) and with improved freedom from progression (p=0.0133). Men with a post-SRT nadir <0.1 ng/ml (undetectable range) had significantly less recurrences (p<0.0001) and a better overall survival (p=0.0248). In multivariate analysis of pre-SRT parameters, pT≥3, Gleason Score ≥7, a post-RP PSA nadir ≥0.1 ng/ml and pre-SRT PSA ≥0.2 ng/ml increased the risk of progression. If failing the post-SRT nadir <0.1 ng/ml was included in the model, then this was the strongest risk factor (hazard ratio 7.93). Conclusions: Our data suggest early salvage RT at a PSA level below 0.2 ng/ml to be a favorable treatment option for post-RP PSA recurrence. It increases the chances of achieving a post-SRT PSA-nadir <0.1 ng/ml, which is associated with an improved outcome in terms of PSA progression and overall survival.
The impact of time to metastasis on survival in treatment-naïve prostate cancer patients.
Authors: Akamatsu Shusuke , Lynch Kenny , Black Peter , Gleave Martin , Goldenberg Larry , Chi Kim N. , So Alan
Published: February 2017

212

Background: With the emergence of novel therapies, the treatment of advanced prostate cancer has evolved. However, patients eventually succumb to their metastatic disease. Nonetheless, little is known about the impact of time to metastasis on survival. To further expand on this, we separated metastatic prostate cancer patients into three groups according to the timing of metastasis and analyzed their survival. Methods: From 2008 to 2013, 157 CRPC patients were identified in our database. Of those, 92 with metastasis and sufficient data were analysed. The patients were classified into three groups according to the timing of metastasis. There were 35 de novo –M (metastasis within three months of initial diagnosis), 26 CSPC-M (initially metastasis free, metastasis found more than 6 months prior to CRPC), and 31 CRPC-M (metastasis found within 6 months of becoming CRPC, or after becoming CRPC). Patient characteristics were analyzed, and survival was calculated. Results: Median follow up were 2.2, 9.6, and 11.8 years for de novo-M, CSPC-M, and CRPC-M. 85 and 84 % in the CSPC-M and CRPC-M respectively had local therapies by surgery and/or radiation. The types of local therapies were similar between the groups. Mean time to PSA recurrence after intial therapy were 3.5 and 2.2 years for CSPC-M and CRPC-M, and median time to metastasis were 4.4 and 11.4 years respectively. Treatments after CRPC included Abiraterone, Enzalutamide, and Docetaxel, and the use of these agents were similar between the groups. Median time to CRPC were 1.4, 6.2, and 8.6 years, and median overall survival after diagnosis were 3.7, 12.3, and 15.8 years for de novo-M, CSPC-M, and CRPC-M. Conclusions: The overall survival and time to CRPC were significantly shorter in de novo-M. Although there was a marked difference in time to metastasis between CSPC-M and CRPC-M, there was no statistically significant difference in overall survival. Either treated with hormone therapy before or after emergence of metastasis, survival of more than 10 years after initial diagnosis is possible.
Metabolic syndrome in castration-resistant prostate cancer patients treated with abiraterone.
Authors: Conteduca Vincenza , Caffo Orazio , Derosa Lisa , Veccia Antonello , Petracci Elisabetta , Chiuri Vincenzo Emanuele , Santoni Matteo , Santini Daniele , Fratino Lucia , Maines Francesca , Testoni Sara , De Giorgi Ugo
Published: February 2017

213

Background: The presence and the impact of metabolic syndrome (MS) in castration-resistant prostate cancer (CRPC) men treated with novel hormonal therapies, as abiraterone, has not still been studied. The study aims to assess the impact of MS on progression free survival (PFS) and overall survival (OS) from time starting abiraterone. Methods: We retrospectively evaluated a consecutive series of metastatic CRPC patients treated with abiraterone after docetaxel failure. MS, as defined by modified Adult Treatment Panel (ATP) III criteria, was assessed at the time of initiation of abiraterone, during treatment and follow-up. Cox regression model was used to evaluate the role of MS on the two end-points. Results: One hundred seventy eight patients had sufficient data to assess the presence of MS. Mean age (± SD) at start of abiraterone was 74.0 ± 7.7 years. Seventy out of 178 patients (39.5%) met MS criteria at baseline, before abiraterone initiation, whereas for eleven patients this occurred during treatment. Median PFS was equal to 5 months for patients with MS versus 9 months for those without MS. Patients with MS had a 2-fold increased risk of progression or death for all causes than patients without MS (HR=1.9, 95% CI [1.3-2.7], P<0.001). Median OS was 16 months and 22 months in patients with and without MS, respectively. After adjusting for covariates, MS resulted not significantly associated to OS (HR=1.2, 95% CI [0.8-1.9], P=0.340). Conclusions: MS may represent a complication of patients treated with abiraterone. The presence of MS appears to be a risk factor for shorter PFS in patients with CRPC treated with abiraterone, even if it does not show any impact on OS, so it needs a further prospective evaluation.
A multidisciplinary clinic to mitigate the impact of androgen deprivation therapy in prostate cancer: A pilot study.
Authors: Aggarwal Rahul Raj , Rodvelt Tammy J. , Rabow Michael W. , Macaire Greta , Fedric Regan , Cortese-Jimenez Geronima , Small Eric Jay
Published: February 2017

218

Background: Androgen deprivation therapy (ADT) increases the risk of numerous metabolic toxicities, including weight and body fat gain, insulin resistance, and osteoporosis. Many of these toxicities can be mitigated with lifestyle changes and monitoring of cardiovascular and diabetes risk factors, however, these are not routinely implemented in clinical practice. We designed a pilot study to evaluate whether a structured multidisciplinary (multi-D) clinic can lessen the metabolic impact of ADT. Methods: Patients who started ADT within the past 6 months were enrolled in the year-long multi-D clinic consisting of monthly face-to-face visits and individualized counseling from registered dietitian, certified exercise physiologist, and symptom management specialist, and assessment of weight, body mass index, percent body fat, fasting glucose, lipids, and hemoglobin A1c on an every 3 month schedule. The primary endpoint for this pilot study was the patient adherence rate to the clinic visit schedule, with a targeted goal of greater than 80%. Secondary endpoints included maximal percent change from baseline in metabolic parameters as outlined above. Results: 22 patients were enrolled between November 2013 and May 2014. Participation in the multi-D clinic was high, with a 95% adherence rate to the clinic schedule. The mean maximal percent change from baseline in metabolic parameters is shown below in the Table. Conclusions: Conducting a multi-D clinic for men receiving ADT was feasible, with an adherence rate of over 90%. The metabolic impact of ADT during the 12-month clinic participation was minimal and compares favorably to historical controls, but may be due to selection bias. A randomized phase 2 study comparing multi-D clinic to usual standard of care is ongoing to validate these findings. [Table: see text]
Androgen deprivation therapy (ADT) and cardiovascular (CV) risk: Analysis of German Statutory Health Insurance (SHI) data.
Authors: Ruessel Christoph , Guthoff-Hagen Susanne , Donatz Verena
Published: February 2017

219

Background: ADT is an established part of the guideline-oriented therapy of prostate cancer (PCa). Concerns regarding increased CV risks associated with ADT were raised by the FDA in 2010. Results from a pooled data-analysis of six prospective randomised trials suggest a lower number of CVevents in patients treated with the GnRH antagonist Degarelix compared with GnRH agonist treated patients with preexisting cardiovascular disease [Albertsen P. et al: Eur Urol 2014; 65: 565-73]. Objective: Can SHI data confirm the observation that the risk for CVevents varies depending on the substance used for ADT. Methods: Retrospective data sets of 4 Mio assured people from SHI funds from the years 2009-2012 were analysed to identify PCa patients treated with ADT, GnRH agonists and GnRH antagonists, respectively. An age-adjusted reference group with 1.1 Mio non-PCa persons was identified in the data sets. Results: 44.166 patients suffering from PCa were identified. Of those 10.611 patients were treated with ADT. 10.554 with GnRH agonists and 132 with GnRH antagonists, respectively. An increased prevalence for relevant baseline CV diseases was observed in ADT treated patients compared to the Non-PCa reference group (diabetes mellitus: 28.66% vs 17.43%.; CAD: 35.77% vs 15.70%; Heart failure: 27.54% vs 9.64%). The rate of heart attack and stroke (CVevents) after treatment begin with ADT was determined: 2.37% in the reference group, 5.9% in the PCa group, 7.8% in the ADT group, 2.3% in the GnRH antagonist group. All CVevents in GnRH antagonist group occurred in high risk patients, only. The urologist examined and reported the state of CV risk for 25% of the PCa patients, only. Urologists examine and treat statistically significantly more patients with a combination of PCa and CVevents than general practitioners (30 vs. 5 per year/per physician). Conclusions: This retrospective analysis confirms the hypothesis that the risk of CVevents varies by using different ADT. The risk might be lower by using GnRH antagonists. A close collaboration of urologists, general practitioners and cardiologists is therefore recommended in the management of PCa patients.
Patient-reported gastrointestinal and genitourinary toxicity after prostate cancer treatment: A comparison between radiotherapy including pelvic nodes and prostate-only radiotherapy.
Authors: Fransson Per , Olofsson Sebastian , Widmark Anders , Thellenberg Karlsson Camilla
Published: February 2017

22

Background: To evaluate side effects of radiotherapy (RT) including the pelvic nodes in patients with prostate cancer. Methods: 143 patients with high risk prostate cancer (Pca) receiving whole pelvic radiotherapy (WPRT) was matched to a group of 142 patients receiving RT towards the prostate and seminal vesicles only (PORT). Both groups were given 78 Gy towards the prostate and 50 Gy towards the seminal vesicles. The WPRT group also received 50 Gy towards the pelvic nodes. WPRT was given with intensity modulated RT or volumetric modulated arc therapy technique and the group treated towards the prostate and seminal vesicles only was treated with 3-dimensional conformal RT. Gastrointestinal (GI) and genitourinary (GU) side effects were evaluated with patient-reported questionnaires and with the RTOG scale, scored by treating physician, at baseline and one-year after RT. Results: Overall the side effects were mild. At one-year follow up there were significant differences regarding morning urgency, mucus- and blood in stool between the two groups (Table 1). The WPRT group expressed lesser complications in all of these cases. In the RTOG GU and GI scores there were no differences between the groups. About 20% had RTOG grade 2 GU score and 2%/1% had RTOG grade 3 score in the PORT and WPRT groups, respectively. The numbers for RTOG grade 2 GI scores were 11% and 5% in the PORT and WPRT groups, respectively. None of the groups reported RTOG grade 3 GI symptoms. Conclusions: Whole pelvic RT can be done with a very satisfying profile of side effects. Sometimes even lesser gastrointestinal reported side effects are seen with the newer techniques compared to prostate only radiotherapy with older techniques. [Table: see text]
Association of baseline perineural invasion with shorter time to progression in men with prostate cancer undergoing active surveillance: Results from the REDEEM study.
Authors: Moreira Daniel M. , Fleshner Neil Eric , Freedland Stephen J.
Published: February 2017

23

Background: Perineural invasion (PNI) on prostate cancer (PC) biopsies has been associated with disease upgrading among those undergoing radical prostatectomy. However, the clinical significance of PNI in men on active surveillance (AS) has been evaluated by a limited number of studies. Thus, we sought to evaluate the association of PNI with time to clinical and pathological progression in men with PC on AS. Methods: Retrospective analysis of 289 men 48 to 82 years old on AS for low-risk PC (T1c-T2a), Gleason ≤6, ≤3 positive cores, ≤50% of any core involved, prostate-specific antigen (PSA) ≤11ng/ml, life expectancy >5 years and follow-up data in the REduction by Dutasteride of clinical progression Events in Expectant Management study. Progression was divided in pathological (>3 positive cores, >50% core involvement or Gleason >6 in a repeat biopsy) or therapeutic (any treatment for PC) or both. Time to progression was analyzed with Kaplan-Meier plots, log-rank tests and Cox model adjusting for age, PSA density, percent cores involved, maximum core involvement and treatment. Results: A total of 11 (4%) patients had PNI on baseline biopsy. PNI was associated with higher tumor length and maximum core involvement (all P<0.05). PNI was not associated with patient’s age, race, PSA levels or density, percent or number of positive cores. After a median follow-up of 37 months, 125 (43%) patients developed progression. Of these, 95 (76%) patients had pathological and 30 (24%) had therapeutic progression. In univariable analysis, patients with baseline PNI had a shorter time to overall and pathological progression (HR=2.62, 95%CI=1.31-5.23, P=0.006 and HR=2.42, 95%CI=1.03-5.66, P=0.041, respectively). Similar results were obtained in multivariable analysis for overall and pathological progression (HR=2.26, 95%CI=1.10-4.68, P=0.028 and HR=2.13, 95%CI=0.88-5.13, P=0.092, respectively). Conclusions: Among patients with PC on AS, PNI is independently associated with shorter time to progression. Thus, PNI may be used to help select patients for AS and stratify them according to the risk of disease progression.
Correlation of baseline serum testosterone (T) and serum prostate-specific antigen (PSA) at 7 months (7 mo PSA) in patients (pts) with new hormone sensitive metastatic prostate cancer (mHSPC) treated with continuous androgen deprivation therapy (cADT).
Authors: Buckley Tyler Howard , Patel Shiven B. , Tantravahi Srinivas Kiran , Batten Julia A. , Stenehjem David D. , Alex Anitha , Agarwal Neeraj
Published: February 2017

231

Background: Based on data from > 1,000 men with new mHSPC undergoing ADT in the SWOG-9346 study, a failure to achieve a 7 mo PSA of ≤4 ng/mL, is a powerful negative predictor of survival (Hussain et al., JCO 2006). Following baseline clinical variables predicted lack of achieving 7 mo PSA ≤ 4.0 ng/mL: increased age, PSA, and bone pain, poor performance status, and Gleason sum ≥ 8. We hypothesized that the baseline serum T is also an independent predictor of 7 mo PSA. Methods: Eligible pts were identified from an institutional database. The association of baseline clinical and disease characteristics with 7 mo PSA were analyzed using multivariate regression model (Table). Results: 54 pts were eligible for inclusion. 44% achieved undetectable 7 mo PSA, and 25% had a 7 mo PSA ≥ 4 ng/mL suggesting a representative population, similar to that in the SWOG-9346 study. Significant association between covariates and 7 mo PSA was observed (Prob > F = 0.0107; R2 = 0.404). Baseline serum T and PSA were independent predictors of 7 mo PSA. Baseline serum T, as a continuous variable, showed negative correlation with 7 mo PSA, while baseline PSA showed a positive correlation (Table). Conclusions: Baseline serum T independently predicts 7 mo PSA. Pts with new mHSPC with lower baseline T may have improved outcomes with deeper androgen blockade with ADT along with a 17,20-lyase and 17-alpha-hydroxylase inhibitor or a second generation androgen receptor inhibitor at the time of induction. Data need further validation in a larger cohort. [Table: see text]
Cabozantinib (C) plus docetaxel (D) and prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Karzai Fatima , Madan Ravi Amrit , Theoret Marc Robert , Arlen Philip M. , Dawson Nancy Ann , Rosner Inger L. , McLeod David G. , Wright John Joseph , Cordes Lisa M , Couvillon Anna , Chun Guinevere , Harold Nancy , Steinberg Seth M. , Trepel Jane B. , Price Douglas K. , Gulley James L. , Figg William Douglas , Dahut William L.
Published: February 2017

235

Background: Docetaxel (D) improves overall survival in metastatic castrate-resistant prostate cancer (mCRPC), but benefits remain short-lived. Clinical data suggests patients (pts) with mCRPC treated with anti-androgen therapy like abiraterone (AA) or enzalutamide (ENZA) have decreased responses to subsequent therapy due to cross-resistance in the androgen pathway targeted by D, AA, or ENZA(van Soest et al, Eur J Cancer 49:18, 2013). Combining D with other agents, like cabozantinib (C), could target different cellular signaling pathways potentially minimizing tumor resistance. Methods: D naive pts receive 75 mg/m2 IV on day 1 of a 21 day cycle, and prednisone (P) 5 mg po q12 hours with C at 3 dose levels: 20, 40, or 60 mg po daily until maximum tolerated dose (MTD) is defined. In phase 2, pts who have progressed on AA or ENZA, enroll on a randomized 2 arm cohort comparing D plus C to D alone. Results: 20 pts have been accrued; 4 at 20 mg C, 8 at 40 mg C, and 7 at 60 mg C. On phase 2, 1 pt is randomized to D alone. Median age is 68 (44-84 yrs). Median baseline PSA is 94.7 (0.01-754.1 ng/mL). Gleason score is 9 (7-10). Median cycles is 9.5 (1-33). 8 pts have bone only disease, 12 pts have bone and soft tissue disease. Common grade 2 and grade 3 adverse events possibly related to C: hand/foot syndrome (4/16), oral mucositis (4/16), hypophosphatemia (4/16), and fatigue (3/16). The MTD of C is 40 mg daily with D. 15 pts were previously treated with AA or ENZA. In 13 patients previously treated with AA, median PFS has not been reached, with a median potential follow up of 12.4 months. Six month PFS is 77.8% and 9 month PFS is 60.5%. Conclusions: D plus P may have limited benefits after disease progression on AA as seen in 3 retrospective analyses demonstrating a median PFS survival of 4.6 months or less (Mezynski J, et al. Ann Oncol 23;11, 2012) (Aggarwal R, et al. Clin Genitourin Cancer 12;5, 2014) (Schweizer MT, et al. Eur Urol 66;4, 2014). PFS results seen in this trial compare favorably to previously published data of treatment with D after AA in mCRPC, suggesting the addition of C to D may help overcome acquired resistance. Further randomized trials will determine if C in combination with D will enhance clinical outcomes. Clinical trial information: NCT01683994.
A novel biomarker signature to predict aggressive disease in African-American men with prostate cancer.
Authors: Yamoah Kosj , Johnson Michael Hiroshi , Choeurng Voleak , Yousefi Kasra , Haddad Zaid , Den Robert Benjamin , Lal Priti , Feldman Michael D , Dicker Adam , Klein Eric A. , Davicioni Elai , Rebbeck Timothy R. , Schaeffer Edward M.
Published: February 2017

24

Background: Numerous studies have reported a significantly higher incidence of PCa and/or adverse pathological features associated with African-American men compared to European-American men. Less however is known about the genomic disparities that exist between these two groups. In this report we compared the race-specific expression of biomarkers linked to PCa pathogenesis in a matched cohort of AA and EA men. Methods: PCa data from AA and EA patients were analyzed from four medical centers. Cases were matched based on CAPRA-S within each institution for a total sample size of 300 (121-AA; 179-EA). The distribution of mRNA expression levels of 20 validated biomarkers associated with PCa initiation and progression was compared by race using a false-discovery-rate adjusted Mann-Whitney U, and logistic regression models. Conditional logistic regression models were used to evaluate the interaction between race and biomarker expression for predicting pathologic T3 PCa. Results: Of 20 biomarkers interrogated, 6 showed statistically significant differential expression in AA compared with EA men in one or more statistical models. These include TMPRSS2-ERG (p<0.001), AMACR (p<0.001), SPINK1 (p=0.005), AR (p=0.018), SRD5A2 (p=0.005), and GSTP1 (p=0.021). Dysregulation of MYCBP (p=0.043) increases risk of pT3 disease in AA but decreases the risk in EA men, while the reverse is true for AMACR (p=0.013), TMPRSS2-ERG (p=0.026), FOXP1 (p=0.016), and GSTP1 (p=0.032). Loss-of-function mutation for tumor suppressors PTEN (p=0.046), TP53 (p=0.042), and RB1 (p=0.027), and dysregulation of AR (p=0.015), EZH2 (p=0.043), NKX3-1 (p=0.024), SRD5A2 (p=0.032), and SPOP (p=0.032) increased risk of pT3 disease for both AA and EA men. Conclusions: We have identified a subset of PCa biomarkers that predict risk of clinico-pathologic outcomes in a race-dependent manner. These biomarkers may in part explain the biological contribution to racial disparity in PCa outcomes between EA and AA men.
Androgen Receptor Modulation Optimized for Response in Splice Variant (ARMOR3-SV): Randomized, open-label, multicenter, controlled study of galeterone versus enzalutamide (enz) in men expressing AR-V7 splice variant (SV), metastatic castrate resistant prostate cancer (mCRPC).
Authors: Roberts Jennifer , Dhillon Reena , Dransfield Daniel T. , Mamlouk Khalid Kevin , Ferrante Karen J.
Published: February 2017

259

Background: Recent data showed that mCRPC patients (pts) with the androgen receptor (AR) SV AR-V7, a truncated form of the AR that lacks the ligand-binding domain and remains a constitutively active transcription factor, had worse clinical outcomes than patients without AR-V7 (Antonarakis et al, NEJM 2014; Efstathiou et al, ASCO 2014; Bambury et al, ESMO 2014). Galeterone, a small molecule, disrupts AR signaling via selective inhibition of CYP17 lyase, competitively inhibits androgen binding to AR, and degrades AR protein. In preclinical models, it demonstrated activity against many AR aberrations, including AR-V7, ARv567es, AR-T878A, and AR-F876L. Given the encouraging results in pts with AR C-terminal loss in the phase 2 ARMOR2 trial (Taplin et al, ESMO 2014), further research is warranted. Methods: ARMOR3-SV is a global, phase 3, randomized, open-label, multicenter, controlled study of galeterone vs enz in men expressing AR-V7 SV–mCRPC. Among other enrollment criteria, eligible pts must have the AR-V7 splice variant, be on GnRH therapy or have had a bilateral orchiectomy with testosterone <50 ng/dL. Approximately <170 pts will be randomized to receive once-daily oral therapy with galeterone 2550 mg or enz 160 mg. The primary endpoint is radiographic progression-free survival. Secondary endpoints include overall survival, time to cytotoxic therapy, and skeletal related events. Pts will be followed until radiographic disease progression as assessed by an independent, blinded radiologic review. Post-progression anticancer interventions will be collected and pts will be followed until death or study termination. Results: Because AR-V7 status must be determined for enrollment, the availability of a validated, accurate, rapid, quantitative, and universally applicable assay performed in a central CLIA-certified laboratory is critical to the trial. Conclusions: Choice of assay to identify and select mCRPC pts harboring AR-V7 is key to enrollment strategy for ARMOR3-SV. The study is expected begin in the first half of 2015.
Subgroup analyses of Japanese patients from the PREVAIL trial of enzalutamide (ENZA) in patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC).
Authors: Kimura Go , Yonese Junji , Fukagai Takashi , Kamba Tomomi , Nishimura Kazuo , Nozawa Masahiro , Mansbach Harry H. , Phung De , Beer Tomasz M. , Tombal Bertrand F. , Ueda Takeshi
Published: February 2017

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Background: In PREVAIL, an international phase 3 randomized trial, treatment with ENZA decreased the risk of radiographic progression or death by 81% and the risk of death by 29% compared with placebo. We evaluated efficacy, safety and pharmacokinetic exposure with ENZA in the Japanese subgroup of patients participating in PREVAIL. Methods: Asymptomatic or mildly symptomatic chemotherapy-naïve patients with mCRPC progressing on androgen deprivation therapies were randomized 1:1 to ENZA 160 mg or placebo until discontinuation upon radiographic progression or initiation of chemotherapy. Continued androgen-deprivation therapy was required. Coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS). Prostate-specific antigen (PSA) response was defined as a confirmed ≥50% reduction from baseline to nadir. Results: A total of 1,717 patients (ENZA: 872, placebo: 845) were randomized in PREVAIL, of which 61 patients were Japanese (ENZA: 28, placebo: 33). The trial was halted after a planned interim analysis at which hazard ratios calculated for OS (0.71; 95%CI: 0.60-0.84) and rPFS (0.19; 95%CI: 0.15-0.23) showed significant benefit of ENZA vs placebo. Hazard ratios for OS and rPFS in Japanese patients were 0.60 (95%CI: 0.20-1.78) and 0.29 (95%CI: 0.030-2.95), respectively. Time to chemotherapy was delayed from a median 10 months on placebo vs not yet reached on ENZA, with a hazard ratio of 0.46 (95%CI: 0.22-0.96). PSA responses were more common in Japanese patients receiving ENZA (61%) vs placebo (21%) (treatment effect = 39.5%; 95%CI: 16.7%-62.3%). Plasma concentration of ENZA was slightly higher in the Japanese subgroup: geometric mean Cmin= 13.8 µg/mL vs 12.3 µg/mL in the non-Japanese cohort at 13 weeks. In the Japanese subgroup adverse events (AEs) ≥ Grade 3 were reported by 9/28 patients (32%) on ENZA vs 13/33 patients (39%) on placebo. Treatment-related AEs ≥ Grade 3 were rare: in the ENZA arm (1/28; 3.6%) and in the placebo arm (2/33; 6.1%). Conclusions: Theefficacy and safety results in the Japanese subgroup were generally consistent with the overall results from the PREVAIL trial. Clinical trial information: NCT01212991.
A phase Ib study of BKM120 combined with abiraterone acetate for castrate-resistant, metastatic prostate cancer.
Authors: Patnaik Akash , Kung Justin , Loda Massimo , Taplin Mary-Ellen , Lis Rosina , Kantoff Philip W. , Balk Steven P. , Bubley Glenn J.
Published: February 2017

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Background: There is cross-talk between PI3-kinase (PI3K) pathway and androgen receptor (AR) signaling pathways, respectively, which are both critical for cell survival in castrate-resistant prostate cancer (CRPC). The primary study objective is to determine the safety profile and MTD of BKM120 (B, pan-PI3K inhibitor) in combination with abiraterone/prednisone (A/P) in CRPC patients. The secondary objectives are to assess the impact of PTEN status on duration of response/time to progression in the expansion cohort, and to evaluate the impact of B on a PI3-kinase activation fingerprint in metastatic bone or lymph node tissue samples. An exploratory objective is to assess the effect of B on transcription of a set of AR-regulated genes in metastatic bone biopsy samples. Methods: The trial design involves a 14 day lead-in phase with B alone, to assess single-agent toxicity and perform correlative studies. A/P is combined with B at the end of 14 days using the standard 3+3 dose-escalation design with 3 dose levels of B, and participants are assessed for safety and MTD on the combination therapy. To determine PD impact of single agent B on the PI3K activation signature at a metastatic site, a mandatory CT-guided bone or lymph node biopsy is performed prior to B initiation and at the end of 2 weeks on B single-agent therapy. Immunohistochemical (IHC) stains for three markers (p-AKT, p-S6 and PTEN) are used to obtain a semi-quantitative PI3K activation score, based on the quartile levels of continuous staining scores of each marker. Results: Patient 1 had symptomatic bone pain improvement, marked decline in narcotic pain requirements and a biochemical decline in PSA from 156.5 to a PSA nadir of 9.2 within 4 weeks of combination therapy. Patient 3 had a symptomatic and >90% biochemical improvement and has currently completed 15 cycles on treatment, and remains on study to date. RT-PCR analysis showed that the feedback circuitry between PI3K and AR signaling is heterogeneous in the metastatic prostate cancer-bone microenvironment, and dependent on tumor PTEN status. Conclusions: Preliminary data shows promising anti-tumor activity in CRPC patients from dual targeting of PI3K and AR pathways with B and A/P, respectively. Clinical trial information: NCT01741753.
Effect of selinexor (KPT-330), a novel oral selective inhibitor of nuclear export (SINE), on tumor suppressors and cell cycle proteins in prostate cancer cells and regression of castration-resistant patient-derived xenograft tumor growth.
Authors: Maity Sankar N. , Wu Guanglin , Lu Jing-Fang , Hoang Anh , Landesman Yosef , McCauley Dilara , Carlson Robert , Rashal Tami , Shacham Sharon , Broom Bradley McIntosh , Baggerly Keith A. , Aparicio Ana , Efstathiou Eleni , Araujo John C. , Logothetis Christopher
Published: February 2017

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Background: Androgen deprivation, anti-androgen and androgen biosynthesis inhibitor treatment can initially control the metastatic prostate cancer (PCa), but treatment-refractory progression frequently follows, with the loss of tumor suppressors (TSPs) and increased expression of cell cycle proteins. Inhibition of the nuclear export protein, Exportin 1 (XPO1) leads to nuclear accumulation of cargo proteins such as TSPs & cell-cycle regulators implicated in castration-resistant PCa (CRPC) progression. XPO1 and specific cargo genes are overexpressed in metastatic CRPC relative to benign & primary prostate tumors, implicating XPO1 activity as playing a role in disease progression. Selinexor (KPT-330), a novel, oral SINE currently in Phase 1/2 for both hematological and solid tumors, has potent activity against CRPC. We hypothesized this activity is due selinexor induced nuclear expression of TSPs. Methods: To test this hypothesis, we treated selected PCa cell lines and patient-derived xenografts (PDXs, two adenocarcinomas and one small cell carcinonoma) with selinexor to determine the effect on survival and cargo protein localization. Results: Treatment with selinexor markedly inhibited PCa cell proliferation in vitro, activated the tumor suppressor TP53 & inhibited cell-cycle regulators. Also, treatment of the PDXs with selinexor for at least 3 weeks significantly inhibited tumor growth & reduced the prostate-specific antigen level in the adenocarcinomas. Selinexor increased cell death in all three PDX tumors and reduced cell proliferation in the adenocarcinomas, but not in the small-cell tumor. Expression analyses demonstrated that selinexor induced nuclear accumulation of different cargo proteins unique to the PCa model, accounting for PDX-specific regression. Conclusions: These results point to an anti-tumorigenic effect of selinexor treatment across a spectrum of hormone-refractory PCa that may provide insight into the drivers of PCa treatment resistance and heterogeneity.
The basal subtype to predict clinical benefit from neoadjuvant chemotherapy: Final results from a phase II clinical trial of DDMVAC plus bevacizumab.
Authors: Siefker-Radtke Arlene O. , Choi Woonyoung , Porten Sima P. , Shen Yu , Kamat Ashish M. , Matin Surena F. , Dinney Colin P. N. , Czerniak Bogdan , McConkey David James
Published: February 2017

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Background: Gene expression profiling (GEP) suggests 3 main subtypes of urothelial cancer: basal, which historically has the worst prognosis with high proliferation and HIF-1 expression; p53-like, with decreased proliferation and increased markers of extracellular matrix (ECM); and luminal which has increased proliferation compared to p53-like tumors. We hypothesized that GEP of transurethral resections (TUR) and cystectomy specimens from patients on a neoadjuvant trial would predict benefit from chemotherapy. Methods: Sixty patients enrolled on a neoadjuvant trial of DDMVAC+B. TUR and cystectomy specimens were available for gene expression profiling in 39 and 33 patients, respectively, with matched specimens in 23 patients. The validation set consisted of 49 patients treated with perioperative MVAC on a previously published clinical trial. Results: Chemotherapy was quite active with pT0N0 and ≤ pT1N0 down-staging rates of 38% and 53%, respectively. Basal tumors had improved survival compared to luminal and p53-like (5-year OS 91%, 73% and 36%, p=0.015). A validation cohort of patients treated with perioperative MVAC confirmed this survival benefit (5-year OS basal, luminal, and p53-like 77%, 57%, and 57%, respectively, p =0.027). The use of bevacizumab in basal tumors did not confirm evidence of significant benefit in these small numbers of patients (5-year OS bevacizumab: 91% vs MVAC: 77%, p=0.68) Bone metastases within 2 years associated exclusively with the p53-like subtype (p53-like: 100%, luminal: 0%, basal 0%, p≤0.001). The p53-like subtype was enriched at cystectomy (basal to p53-like in 3/5 (60%), luminal to p53-like in 5/7 (71%), suggesting chemo-resistance in p53-like tumors. Conclusions: In contrast to historical expectations, the basal subtype was predictive of clinical outcomes from neoadjuvant chemotherapy, reflecting the impact of chemotherapy on highly proliferative tumors. Bone metastases were associated with the p53-like subtype which is enriched for ECM. We can no longer think of urothelial cancer as one disease; subtyping should be considered for all tumors, and may have implications on selecting therapy. Clinical trial information: NCT00506155.
ASCENDE-RT*: A multicenter, randomized trial of dose-escalated external beam radiation therapy (EBRT-B) versus low-dose-rate brachytherapy (LDR-B) for men with unfavorable-risk localized prostate cancer.
Authors: Morris W. James , Tyldesley Scott , Pai Howard H , Halperin Ross , McKenzie Michael R. , Duncan Graeme , Morton Gerard , Murray Nevin , Hamm Jeremy
Published: February 2017

3

Background: This trial compared the efficacy of DE-EBRT and LDR-B for National Comprehensive Cancer Network (NCCN) high and intermediate-risk disease. Methods: A planned sample size of 400 patients were randomized to one of two treatment arms and stratified by risk group. Both arms received 12 months of androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonist plus a non-steroidal anti-androgen for at least 1 month. After 8 months of neo-adjuvant ADT, both arms received whole pelvis EBRT (46Gy/23#). Patients assigned to DE-EBRT (standard arm) then received a conformal EBRT boost (32Gy/16#). Patients assigned to LDR-B (experimental arm) received an Iodine-125 LDR boost prescribed to a minimum peripheral dose of 115Gy. The primary endpoint was relapse free survival (RFS) defined by biochemical criteria using the nadir+2 ng/mL threshold. Time zero was the date of the first LHRH injection. Results: Between Dec 2002 and Sep 2011, 276 high-risk and 122 intermediate-risk patients were accrued at 6 cancer treatment centers. 200 men were assigned to DE-EBRT and 198 to LDR-B. The treatment arms were well balanced in terms of age and known prognostic factors. Median follow up (FU) is 6.5 years; 65 men have >9 years FU. There were 12 major protocol violations in each arm. By intent-to-treat analysis, the 3-, 5-, 7-, and 9-year Kaplan-Meier RFS estimates are 94% vs 94%, 77% vs 89%, 71% vs 86%, and 63% vs 83% for DE-EBRT and LDR-B respectively (hazard ratio = 0.473; 95% CI 0.292 – 0.765; P = 0.0022). Randomization (p<0.001), percent positive cores (p=0.005), initial PSA (p=0.006) and clinical T-stage (p=0.013) were predictive of RFS in a multivariable Cox model. The median PSA at latest FU for non-relapsing patients assigned to LDR-B is 0.02 vs 0.24 ng/mL for DE-EBRT. Conclusions: In a randomized trial, an Iodine-125 LDR boost was much more effective than an EBRT boost in rendering unfavorable-risk prostate cancer patients biochemically disease free. *ASCENDE-RT- Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy is an NCI registered trial (NCT00175396). Clinical trial information: NCT00175396.
Prognostic significance of perineural invasion in localized prostate cancer.
Authors: Lu Louis , Singhal Udit , Skolarus Ted A. , Palapattu Ganesh S. , Montgomery Jeffrey Scott , Weizer Alon Z. , Hollenbeck Brent K. , Miller David Christopher , McNamara Alyssa , Mehra Rohit , Tomlins Scott A. , Hamstra Daniel A. , Morgan Todd Matthew , Feng Felix Yi-Chung
Published: February 2017

30

Background: While perineural invasion (PNI) has been associated with poorer clinical outcomes in prostate cancer patients, it is not well defined as a predictor of long-term endpoints in newly diagnosed prostate cancer. Therefore, we evaluated the role of PNI as a prognostic marker in patients with localized prostate cancer who underwent surgery or radiation. Methods: We analyzed a prospectively collected cohort of 5,034 consecutive patients with localized prostate cancer treated with surgery (n = 4,207) or radiation (n = 827) at University of Michigan from 1994-2013. The primary outcome measured was metastasis-free survival, with secondary outcomes of PSA-recurrence free survival and overall survival (OS). Covariates included age, treatment year, race, comorbidity index, pre-treatment PSA, Gleason score, and T-stage. Survival analysis was estimated using the Kaplan-Meir method, and multivariable analysis was performed using a Cox proportional hazards model. Results: 22.6% of surgery patients and 37.5% of radiation patients had PNI. 169 patients developed metastasis a median of 44 months (IQR 21-83 months) after primary therapy. In the combined cohort, PNI was a predictor of metastasis and PSA recurrence, but not OS (Table 1). For surgery, PNI was a predictor of metastasis, PSA recurrence, and OS. For radiation, PNI was a predictor of metastasis and PSA recurrence, but not OS. Conclusions: PNI is an independent predictor of long-term outcomes in newly diagnosed prostate cancer patients regardless of subsequent therapy. These data support the importance of PNI as a key factor denoting potentially aggressive prostate cancer and importing a significant increase in the likelihood of eventual metastatic progression. [Table: see text]