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Papers by Kim Chi
Journal of Clinical Oncology
PURPOSE The first interim analysis of the phase III, randomized, placebo-controlled TITAN study s... more PURPOSE The first interim analysis of the phase III, randomized, placebo-controlled TITAN study showed that apalutamide significantly improved overall survival (OS) and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving ongoing androgen deprivation therapy (ADT). Herein, we report final efficacy and safety results after unblinding and placebo-to-apalutamide crossover. METHODS Patients with mCSPC (N = 1,052) were randomly assigned 1:1 to receive apalutamide (240 mg QD) or placebo plus ADT. After unblinding in January 2019, placebo-treated patients were allowed to receive apalutamide. Efficacy end points were updated using the Kaplan-Meier method and Cox proportional-hazards model without formal statistical retesting and adjustment for multiplicity. Change from baseline in Functional Assessment of Cancer Therapy-Prostate total score was assessed. RESULTS With a median follow-up of 44.0 months, 405 OS events had occ...
Journal of Clinical Oncology
TPS5101 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that re... more TPS5101 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell signaling and survival pathways implicated in cancer progression and over-expressed in many cancers including prostate, bladder, lung, and breast. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a second-generation antisense oligonucleotide designed to inhibit Hsp27 expression with in vitro and in vivo efficacy that increases apoptosis, inhibits tumor growth, sensitizes cells to chemotherapy and inhibits AR activity (Cancer Res 2007;67(21):10455). A phase 2 study of OGX-427 in patients with mCRPC reported preliminary activity with 50% of patients having a ≥50% PSA decline during treatment (J Clin Oncol 30, 2012 (suppl; abstr 4514)). The purpose of this study was to evaluate the clinical activity of OGX-427 in patients with mCRPC progressing on AA. Methods: In this randomized, phase 2 study,...
Journal of Nuclear Medicine
18 F-DCFPyL (2-(3-{1-carboxy-5-[(6-18 F-fluoro-pyridine-3-carbonyl)amino]-pentyl}-ureido)-pentane... more 18 F-DCFPyL (2-(3-{1-carboxy-5-[(6-18 F-fluoro-pyridine-3-carbonyl)amino]-pentyl}-ureido)-pentanedioic acid), a prostate-specific membrane antigen-targeting radiotracer, has shown promise as a prostate cancer imaging radiotracer. We evaluated the safety, sensitivity, and impact on patient management of 18 F-DCFPyL in the setting of biochemical recurrence of prostate cancer. Methods: Subjects with prostate cancer and biochemical recurrence after radical prostatectomy or curative-intent radiotherapy were included in this prospective study. The subjects underwent 18 F-DCFPyL PET/CT imaging. The localization and number of lesions were recorded. The uptake characteristics of the 5 most active lesions were measured. A pre-and posttest questionnaire was sent to treating physicians to assess the impact on management. Results: One hundred thirty subjects were evaluated. 18 F-DCFPyL PET/CT localized recurrent prostate cancer in 60% of cases with a prostate-specific antigen
Journal of Clinical Oncology
4519^ Background: MDV3100, a novel androgen receptor signaling inhibitor (ARSI), inhibits: 1) bin... more 4519^ Background: MDV3100, a novel androgen receptor signaling inhibitor (ARSI), inhibits: 1) binding of androgens to AR, 2) AR nuclear translocation, and 3) association of AR with DNA. MDV3100 was active in a phase I-II trial enrolling pre- and post-docetaxel castration-resistant prostate cancer (CRPC) patients. The AFFIRM trial evaluated whether MDV3100 could provide benefit to men with post-docetaxel CRPC. Methods: In this double-blind, multinational phase III study, patients who had received docetaxel-based chemotherapy were randomized 2:1 to MDV3100 160 mg/day or placebo. Treatment with corticosteroids was allowed but not required. Patients were stratified by baseline ECOG and mean brief pain inventory score. The primary endpoint was overall survival (OS). Other efficacy endpoints included radiographic progression-free survival (rPFS), time to PSA progression (TTPP), soft tissue objective response (PR+CR), PSA response, and quality of life (QoL) response (FACT-P). Results: 800 patients were randomized to MDV3100 and 399 to placebo with respective median treatment durations of 8.3 and 3.0 months.Based on a planned interim analysis at 520 deaths, the Independent Data Monitoring Committee recommended the study be unblinded and placebo patients offered MDV3100. Efficacy results are presented (Table). The most common MDV3100 events with an incidence higher than placebo were fatigue (34% vs 29%), diarrhea (21% vs 18%), and hot flush (20% vs 10%). Grade >3 events of interest were cardiac disorders (0.9% MDV3100 vs 2% placebo), fatigue (6% MDV3100 vs 7% placebo), seizure (0.6% MDV3100 vs. 0% placebo), and LFT abnormalities (0.4% MDV3100 vs 0.8% placebo). Conclusions: MDV3100, a novel ARSI, is well-tolerated and significantly prolongs OS, slows disease progression, and improves QoL in men with post-docetaxel CRPC. [Table: see text]
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 21, 2018
Several studies have reported that among patients with localized prostate cancer, black men have ... more Several studies have reported that among patients with localized prostate cancer, black men have a shorter overall survival (OS) time than white men, but few data exist for men with advanced prostate cancer. The primary goal of this analysis was to compare the OS in black and white men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in phase III clinical trials with docetaxel plus prednisone (DP) or a DP-containing regimen. Individual participant data from 8,820 men with mCRPC randomly assigned in nine phase III trials to DP or a DP-containing regimen were combined. Race was based on self-report. The primary end point was OS. The Cox proportional hazards regression model was used to assess the prognostic importance of race (black v white) adjusted for established risk factors common across the trials (age, prostate-specific antigen, performance status, alkaline phosphatase, hemoglobin, and sites of metastases). Of 8,820 men, 7,528 (85%) were white, 500 ...
European Urology
Glutathione S-transferase 1 (GSTP1) expression is inactivated in >90% of a... more Glutathione S-transferase 1 (GSTP1) expression is inactivated in >90% of all prostate cancers in association with aberrant DNA methylation. Detection of serum free methylated GSTP1 (mGSTP1) DNA is associated with overall survival (OS) and response to docetaxel in metastatic castration-resistant prostate cancer (mCRPC) in test and internal validation cohorts. To assess the relationship between serum free mGSTP1 and treatment outcomes in SYNERGY, a phase 3 multicentre randomised trial testing the addition of custirsen to first-line chemotherapy with docetaxel in mCRPC. Serum free mGSTP1 DNA was measured by a sensitive methylation-specific polymerase chain reaction assay in paired samples (baseline and after two cycles of docetaxel) from 600 patients. Associations between serum free mGSTP1 at baseline, change in mGSTP1 after docetaxel, OS, and time to prostate-specific antigen (PSA) progression were examined using Cox proportional hazards models and Kaplan-Meier methods. Serum free mGSTP1 was detectable at baseline in 458 (81%) patients. Of those with detectable mGSTP1 at baseline, mGSTP1 became undetectable after two cycles in 243 (53%). Undetectable mGSTP1 at baseline was associated with longer OS (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.29-0.55; p<0.00001). The event of mGSTP1 becoming undetectable after two cycles of chemotherapy was associated with longer OS (HR 0.36, 95% CI 0.29-0.46; p<0.00001) and longer time to PSA progression (HR 0.44, 95% CI 0.35-0.56; p<0.00001). Associations between mGSTP1 and clinical outcomes were independent of other established prognostic variables. Analysis was limited by the lack of radiographic progression-free survival data. This is the first study to externally validate the prognostic role of a circulating epigenetic biomarker in mCRPC. Further studies are needed to validate serum free mGSTP1 as a surrogate endpoint for clinical trials and as a potential clinical decision tool. In this study, we confirmed that a blood marker predicted outcomes after chemotherapy for metastatic prostate cancer. This marker may accelerate future clinical trials of new therapies and be useful in the clinic to guide treatment decisions.
Cell, Jan 26, 2018
While mutations affecting protein-coding regions have been examined across many cancers, structur... more While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivati...
Canadian Urological Association journal = Journal de l'Association des urologues du Canada, 2018
Recently, a prognostic index including six risk factors (RFs) (unfavourable Eastern Cooperative O... more Recently, a prognostic index including six risk factors (RFs) (unfavourable Eastern Cooperative Oncology Group performance status [ECOG PS], presence of liver metastases, short response to luteinizing hormone-releasing hormone [LHRH] agonists/antagonists, low albumin, increased alkaline phosphatase [ALP] and lactate dehydrogenase [LDH]) was developed from the COU-AA-301 trial in post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate. Our primary objective was to evaluate this model in a cohort of chemotherapy-naive mCRPC patients receiving abiraterone. We identified 197 chemotherapy-naive patients who received abiraterone at six BC Cancer Agency centres and who had complete information on all six RFs. Study endpoints were prostate-specific antigen (PSA) response rate (RR), time to PSA progression, time on treatment, and overall survival (OS). PSA RR and survival outcomes were compared using Χ test and log-rank test. Multiv...
The Lancet. Oncology, 2017
Docetaxel and cabazitaxel improve overall survival compared with mitoxantrone in patients with me... more Docetaxel and cabazitaxel improve overall survival compared with mitoxantrone in patients with metastatic castration-resistant prostate cancer. Custirsen (OGX011) is a second generation highly specific antisense oligonucleotide that inhibits the production of clusterin, an antiapoptotic protein that is upregulated in response to chemotherapy and that confers treatment resistance. We aimed to assess whether custirsen in combination with cabazitaxel and prednisone increases overall survival in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel. In this randomised, open-label, international, phase 3 trial, men with radiographically documented metastatic castration-resistant prostate cancer that had progressed after docetaxel treatment with a Karnofsky performance status of more than 70% and who were fit for chemotherapy, were recruited from 95 cancer treatment centres in eight countries. Patients were randomly assigned (1:1) centrally using ...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 31, 2017
Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder canc... more Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer (BCa), but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally-invasive tool to profile the tumor genome in real-time, but is critically under-explored in BCa. <p>Experimental Design: We applied a combination of whole exome sequencing and targeted sequencing across 50 BCa driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive BCa, including 37 with metastatic disease.</p> <p>Results: The majority of metastatic patients, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9 - 72.6%). 12% of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic BCa with 95% of patients harboring deleterious alterations to TP53,...
The New England journal of medicine, Jul 4, 2017
Background Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone... more Background Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. Methods In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. Results After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in ...
![Research paper thumbnail of Corrigendum to 'Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer' [European Journal of Cancer 76 (2017) 36-44]](https://attachments.academia-assets.com/73730992/thumbnails/1.jpg)
](European journal of cancer (Oxford, England : 1990), Aug 10, 2017
Canadian Urological Association journal = Journal de l'Association des urologues du Canada, 2017
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European urology, Jul 1, 2017
Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastati... more Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to androgen receptor (AR)-directed therapy. To determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies and to establish whether biallelic DNA repair gene loss is detectable in matched circulating tumor DNA (ctDNA). We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In patients with deleterious germline mutations, plasma cell-free DNA was also sequenced. Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis. Of the 319 patients, 24 (7.5%) had deleterious germline mutations, with BRCA2 (n=16) being the most frequent. Patients (n=22) with mutat...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 9, 2016
Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effe... more Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride and leuprolide (enza/dut/LHRHa). Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enza or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of prostate-specific antigen (PSA) and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa. In the enza arm, none of the 25 patients achieved pCR or MRD. In th...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2012
183 Background: In study COU-AA-301, the androgen biosynthesis inhibitor AA significantly increas... more 183 Background: In study COU-AA-301, the androgen biosynthesis inhibitor AA significantly increased overall survival in mCRPC post-docetaxel (D) in both interim and updated analyses at 552 and 775 events, respectively. Interim data also showed a significant benefit of AA on patient (pt) reported pain. We present long-term outcomes of the effect of AA on pain and SREs. In this international randomized double blind study of AA (1 g QD) + prednisone (P) (5 mg BID) vs placebo + P in mCRPC post-D, pain was assessed at baseline and each treatment cycle until treatment discontinuation using the BPI-SF questionnaire. Palliation/progression of pain intensity (P-INT) and pain interference (P-INF) were evaluated using a priori definitions. P-INT palliation was defined as ≥ 30% improvement in pt reported "worst pain in last 24 h" (on 0-10 numerical rating scale) durable for ≥ 28 d without increased analgesic use (by WHO criteria) in eligible pts (those with significant baseline pain)....
Investigational new drugs, Dec 26, 2016
Background Docetaxel is a standard first-line treatment option for men with metastatic castration... more Background Docetaxel is a standard first-line treatment option for men with metastatic castration resistant prostate cancer (mCRPC). Sunitinib is attractive as a maintenance therapy due to its mechanism of action, oral route of administration, and acceptable toxicity profile. We designed a phase II study of sunitinib in patients with mCRPC who responded to docetaxel. Methods Patients with responding or stable disease at the completion of docetaxel treatment received 50 mg of sunitinib on 4 week on 2 week off cycles. Treatment continued until disease progression (either by RECIST 1.1 criteria or by cancer related symptomatic progression), intolerable toxicity, start of new cancer therapy, withdrawal of consent, or death. The primary endpoint was progression free survival. Secondary endpoints included PSA response rate and safety. Results Twenty-three patients were enrolled and treated. The mean number of prior cycles of docetaxel given was 8.6 (range 4-12). The median number of cycle...
International journal of urology : official journal of the Japanese Urological Association, Jan 26, 2016
Incorporation of docetaxel into metastatic castration-sensitive prostate cancer treatment has add... more Incorporation of docetaxel into metastatic castration-sensitive prostate cancer treatment has added a new treatment option to a disease state that had previously not seen change for decades. Early attempts of a chemo-hormonal approach for castration-sensitive prostate cancer were not successful. With the demonstration of survival benefits using docetaxel in patients with metastatic castration-resistant prostate cancer, this encouraged continued research with docetaxel given earlier in the disease course. Three randomized phase III trials have defined the benefits of docetaxel in the metastatic castration-sensitive prostate cancer setting; however, there remain questions and controversies on the appropriate and optimal patient selection.
Clinical Cancer Research an Official Journal of the American Association For Cancer Research, Oct 1, 2002
Purpose: The purpose of this study is to evaluate the role of the cell survival gene clusterin in... more Purpose: The purpose of this study is to evaluate the role of the cell survival gene clusterin in radiation-induced cell death in human LNCaP and PC-3 prostate cancer models. Experimental Design: Radiation sensitivities were compared in parental and clusterin-overexpressing LNCaP cells and in PC-3 cells and tumors treated with antisense or mismatch clusterin oligonucleotides. Results: Clusterin-overexpressing LNCaP cells were less sensitive to irradiation with significantly lower cell death rates (23% after 8 Gy) compared with parental LNCaP cells (50% after 8 Gy) 3 days after irradiation. Clusterin expression in PC-3 cells after radiation was found to be up-regulated in a dose-dependent manner in vitro by 70% up to 12 Gy and in vivo by 84% up to 30 Gy. Inhibition of clusterin expression in PC-3 cells using antisense oligonucleotides (ASOs) occurred in a sequence-and dose-dependent manner and significantly enhanced radiation-induced apoptosis and decreased PC-3 cell growth rate and plating efficiency. Compared with mismatch control oligonucleotide treatment, clusterin ASO treatment enhanced radiation therapy and significantly reduced PC-3 tumor volume in vivo by 50% at 9 weeks. In addition, TUNEL staining revealed increased number of apoptotic cells in clusterin ASOtreated and irradiated PC-3 tumors, compared with treatment with mismatch control oligonucleotides plus radiation. Conclusions: These findings support the hypothesis that clusterin acts as a cell survival protein that mediates radioresistance through the inhibition of apoptosis. In vivo results further suggest that inactivation of clusterin using ASO technology might offer a novel strategy to improve results of radiation therapy for prostate cancer patients.
Journal of Clinical Oncology
PURPOSE The first interim analysis of the phase III, randomized, placebo-controlled TITAN study s... more PURPOSE The first interim analysis of the phase III, randomized, placebo-controlled TITAN study showed that apalutamide significantly improved overall survival (OS) and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving ongoing androgen deprivation therapy (ADT). Herein, we report final efficacy and safety results after unblinding and placebo-to-apalutamide crossover. METHODS Patients with mCSPC (N = 1,052) were randomly assigned 1:1 to receive apalutamide (240 mg QD) or placebo plus ADT. After unblinding in January 2019, placebo-treated patients were allowed to receive apalutamide. Efficacy end points were updated using the Kaplan-Meier method and Cox proportional-hazards model without formal statistical retesting and adjustment for multiplicity. Change from baseline in Functional Assessment of Cancer Therapy-Prostate total score was assessed. RESULTS With a median follow-up of 44.0 months, 405 OS events had occ...
Journal of Clinical Oncology
TPS5101 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that re... more TPS5101 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell signaling and survival pathways implicated in cancer progression and over-expressed in many cancers including prostate, bladder, lung, and breast. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a second-generation antisense oligonucleotide designed to inhibit Hsp27 expression with in vitro and in vivo efficacy that increases apoptosis, inhibits tumor growth, sensitizes cells to chemotherapy and inhibits AR activity (Cancer Res 2007;67(21):10455). A phase 2 study of OGX-427 in patients with mCRPC reported preliminary activity with 50% of patients having a ≥50% PSA decline during treatment (J Clin Oncol 30, 2012 (suppl; abstr 4514)). The purpose of this study was to evaluate the clinical activity of OGX-427 in patients with mCRPC progressing on AA. Methods: In this randomized, phase 2 study,...
Journal of Nuclear Medicine
18 F-DCFPyL (2-(3-{1-carboxy-5-[(6-18 F-fluoro-pyridine-3-carbonyl)amino]-pentyl}-ureido)-pentane... more 18 F-DCFPyL (2-(3-{1-carboxy-5-[(6-18 F-fluoro-pyridine-3-carbonyl)amino]-pentyl}-ureido)-pentanedioic acid), a prostate-specific membrane antigen-targeting radiotracer, has shown promise as a prostate cancer imaging radiotracer. We evaluated the safety, sensitivity, and impact on patient management of 18 F-DCFPyL in the setting of biochemical recurrence of prostate cancer. Methods: Subjects with prostate cancer and biochemical recurrence after radical prostatectomy or curative-intent radiotherapy were included in this prospective study. The subjects underwent 18 F-DCFPyL PET/CT imaging. The localization and number of lesions were recorded. The uptake characteristics of the 5 most active lesions were measured. A pre-and posttest questionnaire was sent to treating physicians to assess the impact on management. Results: One hundred thirty subjects were evaluated. 18 F-DCFPyL PET/CT localized recurrent prostate cancer in 60% of cases with a prostate-specific antigen
Journal of Clinical Oncology
4519^ Background: MDV3100, a novel androgen receptor signaling inhibitor (ARSI), inhibits: 1) bin... more 4519^ Background: MDV3100, a novel androgen receptor signaling inhibitor (ARSI), inhibits: 1) binding of androgens to AR, 2) AR nuclear translocation, and 3) association of AR with DNA. MDV3100 was active in a phase I-II trial enrolling pre- and post-docetaxel castration-resistant prostate cancer (CRPC) patients. The AFFIRM trial evaluated whether MDV3100 could provide benefit to men with post-docetaxel CRPC. Methods: In this double-blind, multinational phase III study, patients who had received docetaxel-based chemotherapy were randomized 2:1 to MDV3100 160 mg/day or placebo. Treatment with corticosteroids was allowed but not required. Patients were stratified by baseline ECOG and mean brief pain inventory score. The primary endpoint was overall survival (OS). Other efficacy endpoints included radiographic progression-free survival (rPFS), time to PSA progression (TTPP), soft tissue objective response (PR+CR), PSA response, and quality of life (QoL) response (FACT-P). Results: 800 patients were randomized to MDV3100 and 399 to placebo with respective median treatment durations of 8.3 and 3.0 months.Based on a planned interim analysis at 520 deaths, the Independent Data Monitoring Committee recommended the study be unblinded and placebo patients offered MDV3100. Efficacy results are presented (Table). The most common MDV3100 events with an incidence higher than placebo were fatigue (34% vs 29%), diarrhea (21% vs 18%), and hot flush (20% vs 10%). Grade &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;3 events of interest were cardiac disorders (0.9% MDV3100 vs 2% placebo), fatigue (6% MDV3100 vs 7% placebo), seizure (0.6% MDV3100 vs. 0% placebo), and LFT abnormalities (0.4% MDV3100 vs 0.8% placebo). Conclusions: MDV3100, a novel ARSI, is well-tolerated and significantly prolongs OS, slows disease progression, and improves QoL in men with post-docetaxel CRPC. [Table: see text]
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 21, 2018
Several studies have reported that among patients with localized prostate cancer, black men have ... more Several studies have reported that among patients with localized prostate cancer, black men have a shorter overall survival (OS) time than white men, but few data exist for men with advanced prostate cancer. The primary goal of this analysis was to compare the OS in black and white men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in phase III clinical trials with docetaxel plus prednisone (DP) or a DP-containing regimen. Individual participant data from 8,820 men with mCRPC randomly assigned in nine phase III trials to DP or a DP-containing regimen were combined. Race was based on self-report. The primary end point was OS. The Cox proportional hazards regression model was used to assess the prognostic importance of race (black v white) adjusted for established risk factors common across the trials (age, prostate-specific antigen, performance status, alkaline phosphatase, hemoglobin, and sites of metastases). Of 8,820 men, 7,528 (85%) were white, 500 ...
European Urology
Glutathione S-transferase 1 (GSTP1) expression is inactivated in &amp;amp;amp;gt;90% of a... more Glutathione S-transferase 1 (GSTP1) expression is inactivated in &amp;amp;amp;gt;90% of all prostate cancers in association with aberrant DNA methylation. Detection of serum free methylated GSTP1 (mGSTP1) DNA is associated with overall survival (OS) and response to docetaxel in metastatic castration-resistant prostate cancer (mCRPC) in test and internal validation cohorts. To assess the relationship between serum free mGSTP1 and treatment outcomes in SYNERGY, a phase 3 multicentre randomised trial testing the addition of custirsen to first-line chemotherapy with docetaxel in mCRPC. Serum free mGSTP1 DNA was measured by a sensitive methylation-specific polymerase chain reaction assay in paired samples (baseline and after two cycles of docetaxel) from 600 patients. Associations between serum free mGSTP1 at baseline, change in mGSTP1 after docetaxel, OS, and time to prostate-specific antigen (PSA) progression were examined using Cox proportional hazards models and Kaplan-Meier methods. Serum free mGSTP1 was detectable at baseline in 458 (81%) patients. Of those with detectable mGSTP1 at baseline, mGSTP1 became undetectable after two cycles in 243 (53%). Undetectable mGSTP1 at baseline was associated with longer OS (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.29-0.55; p&amp;amp;amp;lt;0.00001). The event of mGSTP1 becoming undetectable after two cycles of chemotherapy was associated with longer OS (HR 0.36, 95% CI 0.29-0.46; p&amp;amp;amp;lt;0.00001) and longer time to PSA progression (HR 0.44, 95% CI 0.35-0.56; p&amp;amp;amp;lt;0.00001). Associations between mGSTP1 and clinical outcomes were independent of other established prognostic variables. Analysis was limited by the lack of radiographic progression-free survival data. This is the first study to externally validate the prognostic role of a circulating epigenetic biomarker in mCRPC. Further studies are needed to validate serum free mGSTP1 as a surrogate endpoint for clinical trials and as a potential clinical decision tool. In this study, we confirmed that a blood marker predicted outcomes after chemotherapy for metastatic prostate cancer. This marker may accelerate future clinical trials of new therapies and be useful in the clinic to guide treatment decisions.
Cell, Jan 26, 2018
While mutations affecting protein-coding regions have been examined across many cancers, structur... more While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivati...
Canadian Urological Association journal = Journal de l'Association des urologues du Canada, 2018
Recently, a prognostic index including six risk factors (RFs) (unfavourable Eastern Cooperative O... more Recently, a prognostic index including six risk factors (RFs) (unfavourable Eastern Cooperative Oncology Group performance status [ECOG PS], presence of liver metastases, short response to luteinizing hormone-releasing hormone [LHRH] agonists/antagonists, low albumin, increased alkaline phosphatase [ALP] and lactate dehydrogenase [LDH]) was developed from the COU-AA-301 trial in post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone acetate. Our primary objective was to evaluate this model in a cohort of chemotherapy-naive mCRPC patients receiving abiraterone. We identified 197 chemotherapy-naive patients who received abiraterone at six BC Cancer Agency centres and who had complete information on all six RFs. Study endpoints were prostate-specific antigen (PSA) response rate (RR), time to PSA progression, time on treatment, and overall survival (OS). PSA RR and survival outcomes were compared using Χ test and log-rank test. Multiv...
The Lancet. Oncology, 2017
Docetaxel and cabazitaxel improve overall survival compared with mitoxantrone in patients with me... more Docetaxel and cabazitaxel improve overall survival compared with mitoxantrone in patients with metastatic castration-resistant prostate cancer. Custirsen (OGX011) is a second generation highly specific antisense oligonucleotide that inhibits the production of clusterin, an antiapoptotic protein that is upregulated in response to chemotherapy and that confers treatment resistance. We aimed to assess whether custirsen in combination with cabazitaxel and prednisone increases overall survival in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel. In this randomised, open-label, international, phase 3 trial, men with radiographically documented metastatic castration-resistant prostate cancer that had progressed after docetaxel treatment with a Karnofsky performance status of more than 70% and who were fit for chemotherapy, were recruited from 95 cancer treatment centres in eight countries. Patients were randomly assigned (1:1) centrally using ...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 31, 2017
Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder canc... more Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer (BCa), but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally-invasive tool to profile the tumor genome in real-time, but is critically under-explored in BCa. <p>Experimental Design: We applied a combination of whole exome sequencing and targeted sequencing across 50 BCa driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive BCa, including 37 with metastatic disease.</p> <p>Results: The majority of metastatic patients, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9 - 72.6%). 12% of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic BCa with 95% of patients harboring deleterious alterations to TP53,...
The New England journal of medicine, Jul 4, 2017
Background Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone... more Background Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. Methods In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. Results After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in ...
European journal of cancer (Oxford, England : 1990), Aug 10, 2017
Canadian Urological Association journal = Journal de l'Association des urologues du Canada, 2017
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European urology, Jul 1, 2017
Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastati... more Germline mutations in DNA repair genes were recently reported in 8-12% of patients with metastatic castration-resistant prostate cancer (mCRPC). It is unknown whether these mutations associate with differential response to androgen receptor (AR)-directed therapy. To determine the clinical response of mCRPC patients with germline DNA repair defects to AR-directed therapies and to establish whether biallelic DNA repair gene loss is detectable in matched circulating tumor DNA (ctDNA). We recruited 319 mCRPC patients and performed targeted germline sequencing of 22 DNA repair genes. In patients with deleterious germline mutations, plasma cell-free DNA was also sequenced. Prostate-specific antigen response and progression were assessed in relation to initial androgen deprivation therapy (ADT) and subsequent therapy for mCRPC using Kaplan-Meier analysis. Of the 319 patients, 24 (7.5%) had deleterious germline mutations, with BRCA2 (n=16) being the most frequent. Patients (n=22) with mutat...
Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 9, 2016
Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effe... more Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride and leuprolide (enza/dut/LHRHa). Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enza or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of prostate-specific antigen (PSA) and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa. In the enza arm, none of the 25 patients achieved pCR or MRD. In th...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 10, 2012
183 Background: In study COU-AA-301, the androgen biosynthesis inhibitor AA significantly increas... more 183 Background: In study COU-AA-301, the androgen biosynthesis inhibitor AA significantly increased overall survival in mCRPC post-docetaxel (D) in both interim and updated analyses at 552 and 775 events, respectively. Interim data also showed a significant benefit of AA on patient (pt) reported pain. We present long-term outcomes of the effect of AA on pain and SREs. In this international randomized double blind study of AA (1 g QD) + prednisone (P) (5 mg BID) vs placebo + P in mCRPC post-D, pain was assessed at baseline and each treatment cycle until treatment discontinuation using the BPI-SF questionnaire. Palliation/progression of pain intensity (P-INT) and pain interference (P-INF) were evaluated using a priori definitions. P-INT palliation was defined as ≥ 30% improvement in pt reported "worst pain in last 24 h" (on 0-10 numerical rating scale) durable for ≥ 28 d without increased analgesic use (by WHO criteria) in eligible pts (those with significant baseline pain)....
Investigational new drugs, Dec 26, 2016
Background Docetaxel is a standard first-line treatment option for men with metastatic castration... more Background Docetaxel is a standard first-line treatment option for men with metastatic castration resistant prostate cancer (mCRPC). Sunitinib is attractive as a maintenance therapy due to its mechanism of action, oral route of administration, and acceptable toxicity profile. We designed a phase II study of sunitinib in patients with mCRPC who responded to docetaxel. Methods Patients with responding or stable disease at the completion of docetaxel treatment received 50 mg of sunitinib on 4 week on 2 week off cycles. Treatment continued until disease progression (either by RECIST 1.1 criteria or by cancer related symptomatic progression), intolerable toxicity, start of new cancer therapy, withdrawal of consent, or death. The primary endpoint was progression free survival. Secondary endpoints included PSA response rate and safety. Results Twenty-three patients were enrolled and treated. The mean number of prior cycles of docetaxel given was 8.6 (range 4-12). The median number of cycle...
International journal of urology : official journal of the Japanese Urological Association, Jan 26, 2016
Incorporation of docetaxel into metastatic castration-sensitive prostate cancer treatment has add... more Incorporation of docetaxel into metastatic castration-sensitive prostate cancer treatment has added a new treatment option to a disease state that had previously not seen change for decades. Early attempts of a chemo-hormonal approach for castration-sensitive prostate cancer were not successful. With the demonstration of survival benefits using docetaxel in patients with metastatic castration-resistant prostate cancer, this encouraged continued research with docetaxel given earlier in the disease course. Three randomized phase III trials have defined the benefits of docetaxel in the metastatic castration-sensitive prostate cancer setting; however, there remain questions and controversies on the appropriate and optimal patient selection.
Clinical Cancer Research an Official Journal of the American Association For Cancer Research, Oct 1, 2002
Purpose: The purpose of this study is to evaluate the role of the cell survival gene clusterin in... more Purpose: The purpose of this study is to evaluate the role of the cell survival gene clusterin in radiation-induced cell death in human LNCaP and PC-3 prostate cancer models. Experimental Design: Radiation sensitivities were compared in parental and clusterin-overexpressing LNCaP cells and in PC-3 cells and tumors treated with antisense or mismatch clusterin oligonucleotides. Results: Clusterin-overexpressing LNCaP cells were less sensitive to irradiation with significantly lower cell death rates (23% after 8 Gy) compared with parental LNCaP cells (50% after 8 Gy) 3 days after irradiation. Clusterin expression in PC-3 cells after radiation was found to be up-regulated in a dose-dependent manner in vitro by 70% up to 12 Gy and in vivo by 84% up to 30 Gy. Inhibition of clusterin expression in PC-3 cells using antisense oligonucleotides (ASOs) occurred in a sequence-and dose-dependent manner and significantly enhanced radiation-induced apoptosis and decreased PC-3 cell growth rate and plating efficiency. Compared with mismatch control oligonucleotide treatment, clusterin ASO treatment enhanced radiation therapy and significantly reduced PC-3 tumor volume in vivo by 50% at 9 weeks. In addition, TUNEL staining revealed increased number of apoptotic cells in clusterin ASOtreated and irradiated PC-3 tumors, compared with treatment with mismatch control oligonucleotides plus radiation. Conclusions: These findings support the hypothesis that clusterin acts as a cell survival protein that mediates radioresistance through the inhibition of apoptosis. In vivo results further suggest that inactivation of clusterin using ASO technology might offer a novel strategy to improve results of radiation therapy for prostate cancer patients.