Prostate-specific Antigen Response Rate Research Articles

A randomized phase II trial of abiraterone, olaparib or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair defects.

TPS5086 Background: Approximately 20% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in genes encoding DNA repair proteins (e.g. ATM, BRCA1, BRCA2, PALB2, RAD51, CHEK2, FANCA). These mutations impact base excision repair and alternative end-joining, which rely on the activity of poly(ADP-ribose) polymerase (PARP). Olaparib (olap) inhibits PARP and showed activity in a post hoc analysis in mCRPC patients with DNA repair defects (DRD). In a subgroup analysis of the NCI 9012 trial evaluating abiraterone (abi) +/- veliparib (a PARP inhibitor), patients with DRD in both treatment groups had a > 80% prostate-specific antigen (PSA) response rate and prolonged progression free survival (PFS) (13.8 mos vs. 7.8 mos; P = 0.01). Preclinical data suggests interactions between androgen signaling and PARP activity. These observations provide the rationale to evaluate the efficacy of olap, abi or the combination in patients with DRD. Methods: This is a prospective, randomized, open-label phase 2 clinical trial with a primary endpoint of objective PFS (radiographic + clinical). Secondary endpoints: objective disease and PSA response rates. Analysis of tumor specimens, circulating tumor cells/DNA will be performed. Eligible patients with progressive mCRPC, no prior mCRPC therapy with tumor loss of ATM, BRCA1 or BRCA2 (based on known germline loss, prior CLIA certified tumor analysis or new metastatic biopsy) will be stratified by germline vs. somatic mutational status and randomized 1:1:1 to abi (1000 mg daily) + prednisone (5 mg bid), olap (300 mg daily) or olap + abi + prednisone (same doses). Patients in single agent arms may cross over to opposite single agent therapy at progression. An exploratory cohort of patients with DNA repair defects besides ATM, BRCA1, BRCA2 may receive olap. Statistical analysis will provide median, 12-month, and 24-month product-limit estimates of PFS by treatment arm. The study is recruiting 60 randomized patients at sites in the US. The trial is coordinated by the Prostate Cancer Clinical Trials Consortium, LLC and funded by AstraZeneca. Clinical trial information: NCT03012321.

Phase I/II clinical trial to assess safety and efficacy of intratumoral and subcutaneous injection of HVJ-E in castration-resistant prostate cancer patients

Inactivated Sendai virus particles (hemagglutinating virus of Japan envelope (HVJ-E)) have a novel antitumor effect: HVJ-E fused to prostate cancer cells via cell surface receptor causes apoptosis of prostate cancer cells in vitro and in vivo. HVJ-E also induces antitumor immunity by activating natural killer (NK) cells and cytotoxic T cells and suppressing regulatory T cells in vivo. We conducted an open-label, single-arm, phase I/II clinical trial in patients with castration-resistant prostate cancer (CRPC) to determine the safety and efficacy of intratumoral and subcutaneous injection of HVJ-E. Patients with CRPC who were docetaxel-resistant or could not receive docetaxel treatment were eligible. HVJ-E was injected directly into the prostate on day 1 and subcutaneously on days 5, 8 and 12 in two 28-day treatment cycles using a 3+3 dose-escalation design. The primary end points were to evaluate safety and tolerability of HVJ-E. The secondary end points were to analyze tumor immunity and antitumor effect. The study is registered at UMIN Clinical Trials Registry, number UMIN000006142. Seven patients were enrolled, and six patients received HVJ-E. Grade 2 or 3 adverse events (Common Terminology Criteria for Adverse Events Ver. 4.0) were urinary retention and lymphopenia from which the patients recovered spontaneously. No Grade 4 adverse events were observed. Radiographically, three patients had stable disease in the low-dose group, and one patient had stable disease and two had progressive disease in the high-dose group. The prostate-specific antigen (PSA) declined from 14 to 1.9 ng ml−1 in one patient in the low-dose group after two cycles of HVJ-E treatment, and the PSA response rate was 16.6%. NK cell activity was elevated from day 12 to day 28 after HVJ-E administration, whereas serum interleukin-6, interferon (IFN)-α, IFN-β and IFN-γ levels were not affected by HVJ-E treatment. Intratumoral and subcutaneous injections of HVJ-E are feasible and PSA response was observed in a subgroup of CRPC patients.

MP53-02 SERUM TESTOSTERONE LEVEL IS A USEFUL BIOMARKER TO AID OPTIMAL TREATMENT SELECTION IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III1 Apr 2017MP53-02 SERUM TESTOSTERONE LEVEL IS A USEFUL BIOMARKER TO AID OPTIMAL TREATMENT SELECTION IN MEN WITH CASTRATION-RESISTANT PROSTATE CANCER Kohei Hashimoto, Tetsuya Shindo, Hidetoshi Tabata, Toshiaki Tanaka, Jiro Hashimoto, Ryuta Inoue, Takashi Shimizu, Takashi Muranaka, Hiroshi Hotta, Atsushi Takahashi, Masahiro Yanase, and Naoya Masumori Kohei HashimotoKohei Hashimoto More articles by this author , Tetsuya ShindoTetsuya Shindo More articles by this author , Hidetoshi TabataHidetoshi Tabata More articles by this author , Toshiaki TanakaToshiaki Tanaka More articles by this author , Jiro HashimotoJiro Hashimoto More articles by this author , Ryuta InoueRyuta Inoue More articles by this author , Takashi ShimizuTakashi Shimizu More articles by this author , Takashi MuranakaTakashi Muranaka More articles by this author , Hiroshi HottaHiroshi Hotta More articles by this author , Atsushi TakahashiAtsushi Takahashi More articles by this author , Masahiro YanaseMasahiro Yanase More articles by this author , and Naoya MasumoriNaoya Masumori More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1653AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Enzalutamide and abiraterone are frequently used for castration-resistant prostate cancer (CRPC), because of improved tolerability of them compared to taxanes. However, there are no predictive biomarkers to make a decision of how to best use abiraterone or enzalutamide. The aim of this study was to clarify the impact of serum testosterone in a decision-making of treatment selections (enzalutamide or abiraterone) for CRPC. METHODS We retrospectively evaluated consecutive CRPC patients treated at our institution and other satellite hospitals between 2013 and May 2016. A total of 115 patients received enzalutamide or abiraterone for CRPC and had serum testosterone measure at the initiation of the treatment were included in this study. The patients were divided into two groups by serum testosterone before enzalutamide or abiraterone: 54 in the testosterone <5 ng/dl group and 61 in the testosterone ≥5 ng/dl group. Prostate-specific antigen (PSA) response rates (defined as ≥50% PSA declines), PSA progression-free survival (PSA-PFS), and overall survival (OS) were compared between groups. RESULTS A total of 72 patients were treated with enzalutamide and 43 with abiraterone. In the testosterone <5 ng/dl group, the PSA response rates were significantly lower with enzalutamide than that with abiraterone (32% vs. 62%, p=0.033), whereas there was no difference in the testosterone ≥5 ng/dl group (81% vs. 93%, p=0.429). During the median follow-up period of 12 months, 68 men (59%) had PSA relapse. In the testosterone <5 ng/dl group, the median PSA-PFS was significantly lower with enzalutamide than that with abiraterone (2.8 months vs. 6.4 months, p=0.004) (Figure). Likewise, it was significantly lower with enzalutamide than that with abiraterone in the testosterone ≥5 ng/dl group (7.6 months vs. no available, p=0.004) (Figure). Multivariate analysis reveals that testosterone ≥5 ng/dl was an independent predictive factor for PSA-PFS (HR 3.1, p<0.001). However, there was no significant difference in the median OS according to the different testosterone groups. CONCLUSIONS This result suggests that serum testosterone level is a useful biomarker in a decision-making of treatment selections in the novel hormonal therapy for CRPC. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e713 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Kohei Hashimoto More articles by this author Tetsuya Shindo More articles by this author Hidetoshi Tabata More articles by this author Toshiaki Tanaka More articles by this author Jiro Hashimoto More articles by this author Ryuta Inoue More articles by this author Takashi Shimizu More articles by this author Takashi Muranaka More articles by this author Hiroshi Hotta More articles by this author Atsushi Takahashi More articles by this author Masahiro Yanase More articles by this author Naoya Masumori More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP28-17 IMMUNOHISTOCHEMICAL STAINING OF ERG AND SOX9 AS POTENTIAL BIOMARKERS OF DOCETAXEL RESPONSE IN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Markers I1 Apr 2017MP28-17 IMMUNOHISTOCHEMICAL STAINING OF ERG AND SOX9 AS POTENTIAL BIOMARKERS OF DOCETAXEL RESPONSE IN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER Song Wan, Ghee Young Kwon, Jeong Hoon Kim, Joung Eun Lim, Young Hyo Choi, Hyun Woo Chung, Chung Un Lee, Jun Phil Na, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Han Yong Choi, and Hyun Moo Lee Song WanSong Wan More articles by this author , Ghee Young KwonGhee Young Kwon More articles by this author , Jeong Hoon KimJeong Hoon Kim More articles by this author , Joung Eun LimJoung Eun Lim More articles by this author , Young Hyo ChoiYoung Hyo Choi More articles by this author , Hyun Woo ChungHyun Woo Chung More articles by this author , Chung Un LeeChung Un Lee More articles by this author , Jun Phil NaJun Phil Na More articles by this author , Hwang Gyun JeonHwang Gyun Jeon More articles by this author , Byong Chang JeongByong Chang Jeong More articles by this author , Seong Il SeoSeong Il Seo More articles by this author , Seong Soo JeonSeong Soo Jeon More articles by this author , Han Yong ChoiHan Yong Choi More articles by this author , and Hyun Moo LeeHyun Moo Lee More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.830AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Docetaxel-based chemotherapy is recommended as first-line standard of care for metastatic castration-resistant prostate cancer (mCRPC). However, most of the patients developed treatment resistance and experienced treatment-related toxicity. Therefore, we constructed tissue microarrays using prostate biopsy samples and carried out immunohistochemistry (IHC) analyses to evaluate the clinical utility of ERG and SOX9 as potential biomarkers of docetaxel response in mCRPC patients. METHODS We reviewed 71 patients diagnosed with mCRPC and treated with docetaxel (75mg/m2 intravenously, every 3 weeks) between 2001 and 2013. We evaluated the prostate specific antigen (PSA) response rate, PSA progression-free survival (PSA-PFS), clinical/radiologic PFS (C/R-PFS) and the overall survival (OS) based on the recommendations of the Prostate Cancer Working Group 2. The intensities of ERG and SOX9 expression in tumor cells were scored using a four-tiered grading system. A sample with more than 5% of total stained area scoring 2+ or 3+ in intensity was considered to be positive. Kaplan-Meier survival curves were constructed to illustrate the PSA-PFS, C/R-PFS and OS. Multivariate Cox proportional hazard models were utilized to estimate associations between the PSA-PFS, C/R-PFS, OS and risk factors of interest. RESULTS ERG and SOX9 were found in 13 (18.3%) and 62 (87.3%) patients, respectively. ERG-positive had lower PSA response rates than negative (15.4% vs 62.1%, p = 0.004), and SOX9 showed a same trend (46.8% vs 100.0%, p = 0.003). ERG positivity correlated with a lower PSA-PFS (3.2 mos vs 7.4 mos, p < 0.001), C/R-PFS (3.8 mos vs 9.0 mos, p < 0.001) and OS (10.8 mos vs 21.4 mos, p < 0.001). SOX9 positivity also showed a lower PSA-PFS, C/R-PFS and OS (p =0.006, p =0.012 and p =0.023, respectively). On multivariate analysis, ERG positivity was a significant risk factor for a lower PSA-PFS (p < 0.001, hazard ratio (HR): 6.00, 95% confidence interval (CI): 2.96-12.16), C/R-PFS (p < 0.001, HR: 5.50, 95% CI: 2.68-11.29) and OS (p = 0.001, HR: 3.31, 95% CI: 1.66-6.64). In addition, SOX9 was also a significant risk factor for a decreased PSA-PFS (p = 0.018, HR: 2.75, 95% CI: 1.19-6.32), C/R-PFS (p = 0.025, HR: 2.44, 95% CI: 1.12-5.30) and OS (p = 0.047, HR: 4.30, 95% CI: 1.02-18.16). CONCLUSIONS IHC-detected ERG and SOX9 expression is significantly associated with lower PSA-PFS, C/R-PFS and OS in patients with mCRPC treated with docetaxel. They could be used as potential biomarkers for prediction to docetaxel treatment in mCRPC patients. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e345 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Song Wan More articles by this author Ghee Young Kwon More articles by this author Jeong Hoon Kim More articles by this author Joung Eun Lim More articles by this author Young Hyo Choi More articles by this author Hyun Woo Chung More articles by this author Chung Un Lee More articles by this author Jun Phil Na More articles by this author Hwang Gyun Jeon More articles by this author Byong Chang Jeong More articles by this author Seong Il Seo More articles by this author Seong Soo Jeon More articles by this author Han Yong Choi More articles by this author Hyun Moo Lee More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Clinical Outcomes from Androgen Signaling–directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302

In the COU-AA-302 trial, abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling–directed therapies following abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6–not estimable) for subsequent abiraterone acetate plus prednisone and 2.8 mo (range 1.8–not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with abiraterone acetate plus prednisone or enzalutamide for patients who progressed on abiraterone acetate is associated with limited clinical benefit. Patient summaryThis analysis showed limited clinical benefit for subsequent abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent abiraterone acetate plus prednisone or enzalutamide following initial therapy with abiraterone acetate plus prednisone.

Long-term efficacy and safety of enzalutamide (ENZ) monotherapy in hormone-naïve prostate cancer (HNPC): 3-year, open-label, follow-up results.

220 Background: A phase 2 study of the androgen receptor inhibitor ENZ as monotherapy in patients with HNPC [NCT01302041] showed a high prostate-specific antigen (PSA) response rate, regardless of baseline metastases, and favorable tolerability. In a 1- and 2-year follow-up, ENZ maintained long-term reductions from baseline in PSA, with minimal impact on total-body bone mineral density (BMD). Herein, results from a pre-specified 3-year follow-up are reported. Methods: A total of67 patients with HNPC and non-castrate testosterone ( ≥ 230 ng/dL) received ENZ 160 mg/day until disease progression or unacceptable toxicity. The primary end point of PSA response ( ≥ 80% decline from baseline) was analyzed at week 25 and 1, 2, and 3 years. Other end points were best overall tumor response, BMD, body composition, quality of life, and safety. Results: At the 3-year visit, 42 (62.7%) patients remained on the study medication. Of those, 38 (90.5%; 95% confidence interval 77.4%, 97.3%) maintained a PSA response. Of the 26 patients with metastases at baseline, 17 (65.4%) had a complete or partial response as best overall response at 3 years. In patients who completed the 3-year visit, minimal changes from baseline were observed in total-body BMD or in BMD of the femoral neck, trochanter, spine L1–L4, or forearm (median and mean changes ranged from –3.6% to 1.3% and –2.7% to –0.1%, respectively). The EORTC QLQ-C30 global health status results showed a small decrease at 3 years versus baseline (–3.96 points), consistent with the 2-year results. At 3 years, measurements for total body fat increased (median, 14.7%; mean, 16.5%) and total body lean decreased (median, –6.3%; mean, –6.5%) from baseline. Physical functioning, fatigue, and dyspnea worsened ( &gt; 10 points) at 3 years, similar to results at 2 years. The most frequently reported adverse events ( &gt; 10%) were gynecomastia, fatigue, hot flush, nipple pain, hypertension, diarrhea, nausea, pain in extremity, back pain, and constipation. Conclusions: In patients with HNPC treated with ENZ for 3 years, the efficacy of ENZ as monotherapy was maintained. Overall, BMD, global health status, and safety results were similar to those at 2 years. Clinical trial information: NCT01302041.

Efficacy and safety of enzalutamide (ENZA) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with abiraterone acetate (Abi): A multicenter, single-arm, open-label study.

165 Background: This phase 4, multicenter, single-arm, open-label study evaluated the efficacy and safety of ENZA in patients (pts) with progressing mCRPC previously treated with Abi. Methods: All pts maintained castration therapy with luteinizing hormone-releasing hormone for the duration of the trial or had a bilateral orchiectomy. Pts were required to have progressive disease at study entry and ≥ 24 weeks of Abi treatment prior to receiving 160 mg/day ENZA. Prior chemotherapy was allowed. The primary end point was radiographic progression-free survival (rPFS). The secondary end points were overall survival (OS), prostate-specific antigen (PSA) response, and time to PSA progression. Safety was also assessed. Results: A total of215 pts were enrolled; 214 were treated with ENZA (median age, 73 years). The analysis was performed on data up to 48 weeks after the last pt started ENZA treatment. Median duration of prior Abi therapy was 54 weeks. The median duration of ENZA treatment was 5.7 months: 12 months in PSA responders and 4.6 months in non-PSA responders. 16% of pts received treatment for ≥ 1 year. The most common reason for treatment discontinuation was disease progression (65%). Median rPFS was 8.1 months (95% CI 6.1, 8.3). Median OS was not reached in the overall population and 75% of pts were alive 1 year after treatment initiation. PSA response (confirmed or unconfirmed) rate was 26.5% (48/181). The median time to PSA progression was 5.7 months (95% CI 5.6, 5.8). The overall objective response rate in pts with measurable disease at study entry was 12%. The most common treatment emergent adverse events (TEAEs) were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). ENZA was primarily discontinued due to TEAEs in 8% of pts. No seizures were reported. Conclusions: In this study, ENZA remained active in pts with mCRPC previously treated with Abi. Median rPFS in pts with prior chemotherapy was consistent with previously reported data of ENZA in pts with mCRPC and prior chemotherapy/Abi therapy.Reported TEAEs were consistent with the known safety profile of ENZA. Clinical trial information: NCT02116582.

A phase 3, double-blind, randomized placebo-controlled efficacy and safety study of abiraterone acetate in chemotherapy-naïve patients with mCRPC in China, Malaysia, Thailand and Russia

ObjectiveThis double-blind, placebo-controlled phase 3 study was designed to compare efficacy and safety of abiraterone acetate + prednisone (abiraterone) to prednisone alone in chemotherapy-naïve, asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) patients from China, Malaysia, Thailand and Russia. MethodsAdult chemotherapy-naïve patients with confirmed prostate adenocarcinoma, Eastern Cooperative Oncology Group (ECOG) performance status (PS) grade 0–1, ongoing androgen deprivation (serum testosterone <50 ng/dL) with prostate specific antigen (PSA) or radiographic progression were randomized to receive abiraterone acetate (1000 mg, QD) + prednisone (5 mg, BID) or placebo + prednisone (5 mg, BID), until disease progression, unacceptable toxicity or consent withdrawal. Primary endpoint was improvements in time to PSA progression (TTPP). ResultsTotally, 313 patients were randomized (abiraterone: n = 157; prednisone: n = 156); and baseline characteristics were balanced. At clinical cut-off (median follow-up time: 3.9 months), 80% patients received treatment (abiraterone: n = 138, prednisone: n = 112). Median time to PSA progression was not reached with abiraterone versus 3.8 months for prednisone, attaining 58% reduction in PSA progression risk (HR = 0.418; p < 0.0001). Abiraterone-treated patients had higher confirmed PSA response rate (50% vs. 21%; relative odds = 2.4; p < 0.0001) and were 5 times more likely to achieve radiographic response than prednisone-treated patients (22.9% vs. 4.8%, p = 0.0369). Median survival was not reached. Most common (≥10% abiraterone vs. prednisone-treated) adverse events: bone pain (7% vs. 14%), pain in extremity (6% vs. 12%), arthralgia (10% vs. 8%), back pain (7% vs. 11%), and hypertension (15% vs. 14%). ConclusionInterim analysis confirmed favorable benefit-to-risk ratio of abiraterone in chemotherapy-naïve men with mCRPC, consistent with global study, thus supporting use of abiraterone in this patient population.

Parameters predicting for prostate specific antigen response rates at one year post low-dose-rate intraoperative prostate brachytherapy.

PurposeTo develop a model for prostate specific antigen (PSA) values at one year among patients treated with intraoperatively planned 125I prostate brachytherapy (IOPB).Material and methodsFour hundred and deven patients treated with IOPB for prostate adenocarcinoma were divided into four groups: those with PSA values ≥ 3 ng/ml; < 3 and ≥ 2; < 2 and ≥ 1 or PSA < 1 between 10.5 and 14.5 months post implantation (1yPSA). Ordinal regression analysis was then performed between patient, tumor, and treatment characteristics. 1yPSA values were also compared with toxicity outcomes.ResultsMedian 1yPSA was 0.77 (0.04-17.36). Thirty-two patients (8%) had a PSA ≥ 3; 35 (9%) had PSA < 3, ≥ 2; 87 (21%) had PSA < 2, ≥ 1, and most patients 254 (62%) had PSA < 1. PSA response was independent of gland volume, Gleason score, clinical stage, seed activity, V90, V200, D90, or number of needles and seeds used. Older patients had significantly lower 1yPSA; median ages 65.1 (46.5-81.0), 62.1 (50.4-79.5), 60.5 (47.1-80.3), and 58.1 (45.1-74.2) years for each of the 1yPSA groups respectively (p < 0.001). Also, both implant V150 (p < 0.001) and initial PSA values (p = 0.04) were predictive of 1yPSA values. There was no correlation between 1yPSA values and toxicity encountered.ConclusionsPSA response at 1 year post IOPB appears to be dependent on patient age, initial PSA, and implant V150. Our results provide reassurance that parameters other than biochemical failure influence 1yPSA values.

Immunohistochemical staining of ERG and SOX9 as potential biomarkers of docetaxel response in patients with metastatic castration-resistant prostate cancer.

We aimed to evaluate ERG and SOX9 as potential biomarkers of docetaxel response in metastatic castration-resistant prostate cancer (mCRPC) patients. Seventy-one mCRPC patients were evaluated. Tissue microarrays were constructed and immunohistochemistry was performed. Treatment response was assessed by prostate specific antigen (PSA) response rate, PSA progression-free survival (PSA-PFS), clinical/radiologic PFS (C/R-PFS) and overall survival (OS). ERG and SOX9 were found in 13 (18.3%) and 62 (87.3%) patients, respectively. ERG-positive had lower PSA response rates than negative (15.4% vs 62.1%, p = 0.004), and SOX9 showed a same trend (46.8% vs 100.0%, p = 0.003). ERG positivity correlated with a lower PSA-PFS (3.2 mos vs 7.4 mos, p < 0.001), C/R-PFS (3.8 mos vs 9.0 mos, p < 0.001) and OS (10.8 mos vs 21.4 mos, p < 0.001). SOX9 positivity also showed a lower PSA-PFS, C/R-PFS and OS (p =0.006, p =0.012 and p =0.023, respectively). On multivariate analysis, ERG positivity was a significant risk factor for a lower PSA-PFS, C/R-PFS and OS (p < 0.001, p < 0.001 and p =0.001, respectively). SOX9 expression was also a risk factor for a lower PSA-PFS, C/R-PFS and OS (p = 0.018, p = 0.025 and p =0.047, respectively). These findings indicate that ERG and SOX9 is potential biomarkers for prediction to docetaxel treatment in mCRPC patients.

Abstract IA06: Co-Targeting cell cycle and androgen signaling to personalize therapy for hormone dependent prostate cancer

Abstract Prostate cancer (PC) is an androgen driven and dependent disease and androgen deprivation therapy (ADT) is the standard for patients with metastatic hormone sensitive disease. Despite a high response rate, most patients will progress to castration resistance. The expanding molecular knowledge highlights the biologic heterogeneity and adaptive capacity of PC, and provides the rationale for a preemptive multi-targeted therapeutic strategy. Compelling support for the latter strategy is provided by recent data from two randomized trials demonstrating an unprecedented impact on survival with the addition of docetaxel to ADT. Androgens drive proliferation of PC cells via upregulation of cyclin D which complexes with the cyclin-dependent protein kinases 4/6 (CDK4/6) resulting in phosphorylation of retinoblastoma (Rb) tumor suppressor protein and G1/S progression. Alterations in this pathway contribute to progression to castration-resistance. Palbociclib is a novel specific CDK4/ 6 inhibitor which was recently approved in combination with letrozole for postmenopausal women with ER +, HER2 negative advanced breast cancer. In preclinical prostate cancer models, palbociclib inhibited proliferation and promoted G1 arrest in an Rb and Cyclin D dependent manner. Current data indicate that wild-type Rb expression is present in in 95% vs 75% of patients with newly diagnosed vs metastatic castration resistant PC respectively. We estimate that 80-90% of early metastatic hormone-sensitive PC will harbor intact Rb. Based on the biologic and preclinical data, we developed a multicenter randomized phase II clinical trial (NCT02059213) to test the hypothesis that adding palbociclib to ADT in patients with newly metastatic Rb-positive PC will significantly increase the efficacy of ADT. Patients (n = 60) with new metastatic hormone sensitive PC and Rb intact tumors based on metastatic biopsy are stratified by disease extent and randomized (1:2) to ADT or ADT+ palbociclib. Primary endpoint is confirmed prostate specific antigen (PSA) response (&amp;lt; 4 ng/mL) after 28 weeks of therapy. With 20 patients randomized to ADT and 40 randomized to ADT plus palbociclib there will be a 64.2% power to detect a 20% difference in proportions with a one-sided type I error of 0.10 using the mid p-value method of the Fisher's exact test. Secondary endpoints: safety and tolerability of ADT + palbociclib, rate of undetectable PSA (&amp;lt; 0.2ng/mL), biochemical and clinical progression-free survival, overall PSA and radiographic response rates, assessment of biomarkers which predict therapy response (circulating DNA and tumor cells, tumor protein and transcriptome analysis) and to establish a repository of metastatic hormone sensitive prostate tumor samples. To date 39 patients have been registered and underwent tumor metastatic disease biopsy (soft tissue 26, bone 13). 2 patients were Rb negative and 5 had inadequate tissue. 32 patients have been randomized to ADT (11 patients) or ADT + palbociclib (21 patients). The study is in progress. Support: Movember-PCF Challenge Award, Pfizer. Citation Format: Maha Hussain, Phillip L. Palmbos1, Scott A. Tomlins1, Stephanie Daignault-Newton, Neeraj Agarwal, Przemyslaw Twardowski, Alicia K. Morgans, Emmanuel S. Antonarakis, Karen E. Knudsen, Felix Y. Feng. Co-Targeting cell cycle and androgen signaling to personalize therapy for hormone dependent prostate cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA06.

Systemic Immune-Inflammation Index Predicts the Clinical Outcome in Patients with mCRPC Treated with Abiraterone.

Background: A systemic immune-inflammation index (SII) based on neutrophil (N), lymphocyte (L), and platelet (P) counts has shown a prognostic impact in several solid tumors. The aim of this study is to evaluate the prognostic role of SII in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone post docetaxel.Patients and Methods: We retrospectively reviewed consecutive mCRPC patients treated with abiraterone after docetaxel in our Institutions. X-tile 3.6.1 software, cut-off values of SII, neutrophil-to-lymphocyte ratio (NLR) defined as N/L and platelets-to-lymphocyte ratio (PLR) as P/L. Overall survival (OS) and their 95% Confidence Intervals (95% CI) was estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of SII, PLR, and NLR on overall survival (OS) was evaluated by Cox regression analyses and on prostate-specific antigen (PSA) response rates were evaluated by binary logistic regression.Results: A total of 230 mCRPC patients treated abiraterone were included. SII ≥ 535, NLR ≥ 3 and PLR ≥ 210 were considered as elevated levels (high risk groups. The median OS was 17.3 months, 21.8 months in SII < 535 group and 14.7 months in SII ≥ 535 (p < 0.0001). At univariate analysis Eastern Cooperative Oncology Group (ECOG) performance status, previous enzalutamide, visceral metastases, SII, NLR, and PLR predicted OS. In multivariate analysis, ECOG performance status, previous enzalutamide, visceral metastases, SII, and NLR remained significant predictors of OS [hazard ratio (HR) = 5.08, p < 0.0001; HR = 2.12, p = 0.009, HR = 1.77, 95% p = 0.012; HR = 1.80, p = 0.002; and HR = 1.90, p = 0.001, respectively], whereas, PLR showed a borderline ability only (HR = 1.41, p = 0.068).Conclusion: SII and NLR might represent an early and easy prognostic marker in mCRPC patients treated with abiraterone. Further studies are needed to better define their impact and role in these patients.

Chemotherapy with or without estramustine for treatment of castration-resistant prostate cancer: A systematic review and meta-analysis.

Background:Recently, increasing relevant studies researched the efficacy of castration resistant prostate cancer (CRPC) patients using chemotherapy with or without estramustine, in order to assess the efficacy and toxicity of combining estramustine with chemotherapy for the treatment of CRPC.Methods:Relevant randomized clinical trials were systematically searched from the databases Pubmed, Embase, and Web of science up to April 1, 2016. Data were centrally extracted and analyzed from the previous studies by 2 independent reviewers. The primary endpoint was overall survival (OS) with pooled hazard ratios. Secondary endpoints were prostate-specific antigen (PSA) response and grade 3 or 4 toxicity using pooled odds ratios. Stata version 12.0 software was used for statistical analysis.Results:Overall, this meta-analysis identified 9 eligible articles, including a total of 956 patients, who had been accrued between January 1, 1993 and December 1, 2010 and randomly divided into chemotherapy with estramustine and without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, epirubicin, and vinblastine. Patients who received chemotherapy with estramustine had a better improvement in PSA response rate, comparing those without estramustine (OR = 1.84, 95% CI = 1.20–2.80). However, OS between the 2 groups indicated no significant differences (HR = 0.90, 95% CI = 0.77–1.05). Besides, these results of meta-analysis showed no obvious differences between these 2 groups in grade 3 or 4 adverse effects, including anemia (OR = 0.78, 95% CI = 0.38–1.57), neutropenia (OR = 0.91, 95% CI = 0.59–1.43), thrombocytopenia (OR = 0.68, 95% CI = 0.19–2.42), nausea (OR = 2.34, 95% CI = 0.81–6.72), vomiting (OR = 2.43, 95% CI = 0.69–8.51), diarrhea (OR = 3.45, 95% CI = 0.93–12.76), fatigue (OR = 0.67, 95% CI = 0.32–1.41), neuropathy (OR = 0.54, 95% CI = 0.21–1.44), allergic reaction (OR = 1.60, 95% CI = 0.37–6.84), thromboembolic event (OR = 2.18, 95% CI = 0.86–5.51), and edema (OR = 1.02, 95% CI = 0.18–5.95).Conclusions:This meta-analysis indicated chemotherapy with additional estramustine increased the PSA response rate. However, OS and grade 3 or 4 toxicity were not improved for these patients with CRPC.

Efficacy of metronomic oral cyclophosphamide with low dose dexamethasone and celecoxib in metastatic castration-resistant prostate cancer.

This study aimed to assess the efficacy and safety of oral metronomic chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC). From January 2011 to February 2013, 60 patients with mCRPC received daily metronomic oral cyclophosphamide (50 mg qd), dexamethasone (1 mg qd) and celecoxib (200 mg bid). Among them 49 patients who met the preset inclusion criteria were included in this retrospective study. Adverse events and activity for reducing serum prostate-specific antigen (PSA) levels, Response Evaluation Criteria in Solid Tumor responses and symptomatic responses were reviewed. The primary endpoints were PSA response rate and time to PSA progression (TTPSA). Twenty-two patients had previous exposure to docetaxel. The median age was 71 years (range, 49-88) with a median Eastern Cooperative Oncology Group performance of 1 (range, 0-2). The Gleason score was 8 or more in 41 patients (84%) with a median baseline serum PSA of 32.1 ng/mL (range, 1.2-743.0). The PSA response rate was 39%. With a median follow-duration of 17.5 months, the median TTPSA was 5.2 months (95% CI: 3.1-7.4). The median time to composite progression was 3.9 months (95% CI: 2.2-5.6) and a median overall survival was 13.3 months (95% CI: 9.5-17.1 months). There were no significant differences in the TTPSA between the pre- and post-docetaxel groups. Grade 3-4 AEs occurred only in six patients. Metronomic oral cyclophosphamide chemotherapy is safe, well-tolerated and shows promising activity against mCRPC.

Persistent Neutrophil to Lymphocyte Ratio >3 during Treatment with Enzalutamide and Clinical Outcome in Patients with Castration-Resistant Prostate Cancer.

The baseline value of neutrophil to lymphocyte ratio (NLR) has been found to be prognostic in patients with metastatic castration resistant prostate cancer (CRPC). We evaluated the impact of baseline NLR and its change in patients receiving enzalutamide. We included consecutive metastatic CRPC patients treated with enzalutamide after docetaxel and studies the change of NLR (>3 vs ≤3) after week 4 and 12 weeks. Progression-free survival (PFS), overall survival (OS) and their 95% Confidence Intervals (95% CI) were estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of NLR on PFS and OS was evaluated by Cox regression analyses and on prostate-specific antigen response rates (PSA RR; PSA decline >50%) were evaluated by binary logistic regression. Data collected on 193 patients from 9 centers were evaluated. Median age was 73.1 years (range, 42.8–90.7). The median baseline NLR was 3.2. The median PFS was 3.2 months (95% CI = 2.7–4.2) in patients with baseline NLR >3 and 7.4 months (95% CI = 5.5–9.7) in those with NLR ≤3, p < 0.0001. The median OS was 10.4 months (95% CI = 6.5–14.9) in patients with baseline NLR >3 and 16.9 months (95% CI = 11.2–20.9) in those with baseline NLR ≤3, p < 0.0001. In multivariate analysis, changes in NLR at 4 weeks were significant predictors of both PFS [hazard ratio (HR) 1.24, 95% confidence interval (95% CI) 1.07–1.42, p = 0.003, and OS (HR 1.29, 95% CI 1.10–1.51, p = 0.001. A persistent NLR >3 during treatment with enzalutamide seems to have both prognostic and predictive value in CRPC patients.

AR-V7 Transcripts in Whole Blood RNA of Patients with Metastatic Castration Resistant Prostate Cancer Correlate with Response to Abiraterone Acetate

The expression of AR-V7 (androgen receptor splice variant) 7 in circulating tumor cells has been associated with resistance to abiraterone and enzalutamide in patients with metastatic castration resistant prostate cancer. We used a sensitive, whole blood reverse transcriptase-polymerase chain reaction assay that does not require circulating tumor cell enrichment to correlate outcomes of abiraterone with whole blood expression of AR-V7 and other prostate cancer associated transcripts. We assessed the expression of AR-V7, FOXA1, GRHL2, HOXB13, KLK2, KLK3 and TMPRSS2:ERG mRNA in 2.5 ml whole blood from each of 27 patients with metastatic castration resistant prostate cancer and 33 controls without cancer as the discovery cohort. Cycle threshold values of controls with the highest gene expression were set as the threshold for a positive test. Thresholds were then applied to a validation cohort of 37 patients with metastatic castration resistant prostate cancer who were commencing abiraterone. Gene expression was correlated with the prostate specific antigen response rate using the chi-square test, and with time to prostate specific antigen progression and overall survival using the log rank test. In the discovery cohort 3 of 27 patients (11.1%) with metastatic castration resistant prostate cancer were AR-V7 positive vs 4 of 37 (10.8%) in the validation cohort. In the validation cohort patients with a positive AR-V7 test had a lower prostate specific antigen response rate (0% vs 42%, p = 0.27) together with shorter median prostate specific antigen progression (0.7 vs 4.0months, p <0.001) and median overall survival (5.5 vs 22.1 months, p<0.001). Reverse transcriptase-polymerase chain reaction detection of AR-V7 transcripts in whole blood was associated with inferior outcomes in patients treated with abiraterone. These results reinforce the potential usefulness of AR-V7 as a prognostic and predictive biomarker for metastatic castration resistant prostate cancer.

Comparative Assessment of Clinical Outcomes Between Abiraterone Acetate and Enzalutamide in Patients With Docetaxel-Naive Metastatic Castration-Resistant Prostate Cancer: Experience in Real-World Clinical Practice in Japan

BackgroundThe objective of the present study was to comprehensively compare the clinical outcomes between abiraterone acetate (AA) and enzalutamide (Enz) in Japanese patients with docetaxel-naive metastatic castration-resistant prostate cancer (mCRPC). Patients and MethodsThe present study retrospectively included 280 consecutive mCRPC patients, consisting of 113 and 167 who had received AA and Enz, respectively, without previous treatment with docetaxel. ResultsOf the several baseline characteristics examined, some parameters, including performance status (PS), prostate-specific antigen (PSA) value, and incidence of lymph node metastasis, significantly favored the Enz over the AA group. The PSA response rate in the Enz group was significantly greater than that in the AA group, and the PSA progression-free survival in the Enz group was significantly superior to that in the AA group. Multivariate analyses of several parameters identified the following independent predictors of PSA progression-free survival: duration of androgen deprivation therapy and PS for the AA group, age and PS for the Enz group, and PS but not the introduced agent (ie, AA vs. Enz) for the overall patients. The common adverse events observed in the present series were fatigue (19.4%) and liver toxicity (11.5%) in the AA group and fatigue (32.3%) and appetite loss (19.2%) in the Enz group. In addition, the proportion of patients with adverse events grade ≥ 3 in the Enz group (11.4%) was significantly greater than that in the AA group (4.4%). ConclusionBoth AA and Enz were effective and tolerable for patients with docetaxel-naive mCRPC in the routine clinical setting.

Indirect comparison between abiraterone acetate and enzalutamide for the treatment of metastatic castration-resistant prostate cancer: a systematic review

This study was designed to evaluate the efficacy, tolerability, and sequential administration of abiraterone acetate (AA) and enzalutamide (Enz) for metastatic castration-resistant prostate cancer (mCRPC). A literature search was performed with PubMed, Embase, and Web of Science databases to identify relevant studies. Reviewed literature included published phase III trials of AA or Enz in mCRPC and studies regarding their sequential administration. Given the difference in control arms in AA (active comparator) and Enz (true placebo) randomized phase III studies, indirect comparisons between AA and Enz in mCRPC showed no statistically significant difference in overall survival in prechemotherapy and postchemotherapy settings (HR: 0.90, 95% CI, 0.73–1.11; HR: 0.85, 95% CI, 0.68–1.07). Compared with AA, Enz may better outperform control arms in treating mCRPC both before and after chemotherapy regarding secondary endpoints based on indirect comparisons: time to prostate-specific antigen (PSA) progression (HR: 0.34, 95% CI, 0.28–0.42; HR: 0.40, 95% CI, 0.30–0.53), radiographic progression-free survival (HR: 0.37, 95% CI, 0.28–0.48; HR: 0.61, 95% CI, 0.50–0.74), and PSA response rate (OR: 18.29, 95% CI, 11.20–29.88; OR: 10.69, 95% CI, 3.92–29.20). With regard to the effectiveness of Enz following AA or AA following Enz, recent retrospective case series reported overall survival and secondary endpoints for patients with mCRPC progression after chemotherapy. However, confirmatory head-to-head trials are necessary to determine the optimal sequencing of these agents.

Genomic Alterations in Cell-Free DNA and Enzalutamide Resistance in Castration-Resistant Prostate Cancer

The molecular landscape underpinning response to the androgen receptor (AR) antagonist enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) is undefined. Consequently, there is an urgent need for practical biomarkers to guide therapy selection and elucidate resistance. Although tissue biopsies are impractical to perform routinely in the majority of patients with mCRPC, the analysis of plasma cell-free DNA (cfDNA) has recently emerged as a minimally invasive method to explore tumor characteristics. To reveal genomic characteristics from cfDNA associated with clinical outcomes during enzalutamide treatment. Plasma samples were obtained from August 4, 2013, to July 31, 2015, at a single academic institution (British Columbia Cancer Agency) from 65 patients with mCRPC. We collected temporal plasma samples (at baseline, 12 weeks, end of treatment) for circulating cfDNA and performed array comparative genomic hybridization copy number profiling and deep AR gene sequencing. Samples collected at end of treatment were also subjected to targeted sequencing of 19 prostate cancer-associated genes. Enzalutamide, 160 mg, daily orally. Prostate-specific antigen response rate (decline ≥50% from baseline confirmed ≥3 weeks later). Radiographic (as per Prostate Cancer Working Group 2 Criteria) and/or clinical progression (defined as worsening disease-related symptoms necessitating a change in anticancer therapy and/or deterioration in Eastern Cooperative Group performance status ≥2 levels). The 65 patients had a median (interquartile range) age of 74 (68-79) years. Prostate-specific antigen response rate to enzalutamide treatment was 38% (25 of 65), while median clinical/radiographic progression-free survival was 3.5 (95% CI, 2.1-5.0) months. Cell-free DNA was isolated from 122 of 125 plasma samples, and targeted sequencing was successful in 119 of 122. AR mutations and/or copy number alterations were robustly detected in 48% (31 of 65) and 60% (18 of 30) of baseline and progression samples, respectively. Detection of AR amplification, heavily mutated AR (≥2 mutations), and RB1 loss were associated with worse progression-free survival, with hazard ratios of 2.92 (95% CI, 1.59-5.37), 3.94 (95% CI, 1.46-10.64), and 4.46 (95% CI, 2.28-8.74), respectively. AR mutations exhibited clonal selection during treatment, including an increase in glucocorticoid-sensitive AR L702H and promiscuous AR T878A in patients with prior abiraterone treatment. At the time of progression, cfDNA sequencing revealed mutations or copy number changes in all patients tested, including clinically actionable alterations in DNA damage repair genes and PI3K pathway genes, and a high frequency (4 of 14) of activating CTNNB1 mutations. Clinically informative genomic profiling of cfDNA was feasible in nearly all patients with mCRPC and can provide important insights into enzalutamide response and resistance.

Efficacy, quality of life, and safety of cabazitaxel in Canadian metastatic castration-resistant prostate cancer patients treated or not with prior abiraterone.

In the TROPIC study, cabazitaxel improved overall survival in abiraterone-naïve metastatic castration-resistant prostate cancer (mCRPC) patients post-docetaxel. To evaluate cabazitaxel in routine clinical practice, an international, single-arm trial was conducted. Efficacy, safety, and quality of life (QoL) data were collected from Canadian patients enrolled. Overall survival and progression-free survival were not collected as part of this study. Importantly, prior abiraterone use was obtained and its impact on clinical parameters was examined. Sixty-one patients from nine Canadian centres were enrolled, with prior abiraterone use known for 60 patients. Prostate-specific antigen (PSA) response rate, safety, and impact on QoL life were analyzed as a function of prior abiraterone use. Overall, 92% of patients were ECOG 0/1, 88% had bone metastases, and 25% visceral metastases. Patients treated without prior abiraterone (NoPriorAbi) (n=35, 58%) and with prior abiraterone (PriorAbi) (n=25, 42%) had similar baseline characteristics, except for age and prior cumulative docetaxel dose. Median number of cabazitaxel cycles received was similar between groups (NoPriorAbi=6, PriorAbi=7), as was PSA response rate (NoPriorAbi=36.4%, PriorAbi=45.0%, p=0.54). Almost one-third (31%) of patients received prophylactic granulocyte colony-stimulating factors. Most frequent Grade 3/4 toxicities were neutropenia (14.8%); anemia, febrile neutropenia, fatigue (each at 9.8%); and diarrhea (8.2%). No treatment-related adverse event leading to death was observed. QoL and pain were improved with no difference seen between groups. Treatment discontinuation was mainly due to disease progression (45.9%) and adverse events (32.8%). In routine clinical practice, cabazitaxel's risk-benefit ratio in mCRPC patients previously treated with docetaxel seems to be maintained independent of prior abiraterone use.