Randomised phase 3 trial of enzalutamide in androgen deprivation therapy (ADT) with radiation therapy for high risk, clinically localized prostate cancer: ENZARAD (ANZUP 1303).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS156-TPS156
Author(s):  
Scott Williams ◽  
Ian D. Davis ◽  
Christopher Sweeney ◽  
Martin R. Stockler ◽  
Andrew James Martin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Open Label ◽  
Phase 3 ◽  
Free Survival ◽  
Castration Resistant ◽  
Psa Progression

TPS156 Background: Adjuvant ADT with an LHRH analog (LHRHA) given before, during and after radiotherapy (RT) is standard of care for high risk localised prostate cancer (PC). Enzalutamide improves overall survival (OS) in castration-resistant, metastatic prostate cancer. We hypothesized that the addition of enzalutamide to adjuvant ADT and RT will improve outcomes. The aim is to determine the effects of enzalutamide versus a conventional non-steroidal anti-androgen (NSAA) as part of neoadjuvant and adjuvant ADT in men undergoing RT for high risk, localized PC. Methods: DESIGN: Open label, randomised, phase 3 trial including ANZ, USA, UK, Ireland and Europe. ENDPOINTS: OS (primary), cause-specific survival, PSA progression free survival (PFS), clinical PFS, time to subsequent hormonal therapy, time to castration-resistant disease (PCWG2 criteria), metastasis free survival (MFS), adverse events and health-related quality of life (HRQOL). CORRELATIVE OBJECTIVES: identification of prognostic/predictive biomarkers from archival tumour tissue and serial blood samples. SAMPLE SIZE: 800 participants with a minimum follow-up of 5.5 yrs is designed to give 80% power to detect 33% reduction in the hazard of death assuming 5-year survival rate of 76% amongst controls. TREATMENT: Enzalutamide 160mg daily for 24 months versus conventional NSAA for 6 months. All participants receive LHRHA for 24 months, and RT starting about week 16 delivered as 78Gy in 39#, or 46Gy in 23# plus brachytherapy (nodal RT optional for N0, mandatory for N1). ASSESSMENTS: Baseline, then every 8 weeks until year 2, then 3-4 monthly until year 5, 6-monthly until year 7, then annually. Imaging with CT/MRI and bone scan at baseline, PSA progression, then 6 monthly until re-initiation of ADT, when PCWG2 criteria for CRPC are met and then 3 monthly until evidence of metastases. 623 participants recruited from 61 sites as of 16 October 2017. ENZARAD is an investigator-initiated cooperative group trial led by ANZUP Cancer Trials Group with funds and product from Astellas. Clinical trial information: NCT02446444.

Randomised phase III trial of enzalutamide in androgen deprivation therapy (ADT) with radiation therapy for clinically localised, high risk, or node-positive prostate cancer: ENZARAD (ANZUP 1303).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS5096-TPS5096
Author(s):  
Scott Williams ◽  
Ian D. Davis ◽  
Christopher Sweeney ◽  
Martin R. Stockler ◽  
Andrew James Martin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Predictive Biomarkers ◽  
Standard Of Care ◽  
Phase Iii ◽  
Open Label ◽  
Node Positive ◽  
Resistant Disease ◽  
Castration Resistant ◽  
Psa Progression

TPS5096 Background: Adjuvant ADT with an LHRH analog (LHRHA) given before, during and after radiotherapy (RT) is standard of care for high risk localised prostate cancer (PC). Enzalutamide is more effective in metastatic disease than conventional non-steroidal anti-androgens (NSAA). We hypothesize that addition of enzalutamide to adjuvant ADT and RT will improve outcomes. The aim is to determine the efficacy of enzalutamide compared with NSAA as part of adjuvant ADT with LHRHA in men planned for RT for localized high risk or node-positive PC. Methods: DESIGN: Open label, randomised, phase 3 trial including ANZ, USA, UK, Ireland and Europe. ENDPOINTS: OS (primary), cause-specific survival, PSA PFS, clinical PFS, time to subsequent hormonal therapy, time to castration-resistant disease (PCWG2 criteria), metastasis free survival, adverse events and HRQOL. Tertiary objectives: identification of prognostic/predictive biomarkers from archival tumour tissue and 4 serial fasting bloods. 800 target participants with 5.5 yrs minimum follow-up. 80% power to detect 33% reduction in the hazard of death assuming 5-year survival rate of 76% amongst controls. TREATMENT: Participants are randomised 1:1 to enzalutamide 160mg daily for 24 months versus conventional NSAA for 6 months. All participants receive LHRHA for 24 months and RT starting after week 16. RT delivered as 78Gy in 39 Fx or 46Gy in 23 Fx plus brachytherapy (nodal RT optional for N0, mandatory for N1). ASSESSMENTS: Baseline, then every 8 weeks until year 2, then 3-4 monthly until year 5, 6-monthly until year 7, then annually. CT/MRI and bone scan at baseline, PSA progression, 6 monthly until re-initiation of ADT, when PCWG2 criteria for CRPC are met and then 3 monthly until evidence of metastases. As of 1st February 2017, 55 of 67 sites open with 398 patients recruited. EORTC sites expected to open from Quarter 1 2017. ENZARAD is an investigator-initiated cooperative group trial led by ANZUP Cancer Trials Group with funds and product from Astellas. ANZUP is supported by Cancer Australia and previously CI NSW. ClinicalTrials.gov: NCT02446444, ANZCTR: ACTRN12614000126617 Clinical trial information: NCT02446444.

scholarly journals A phase 3 randomised study of enzalutamide plus leuprolide and enzalutamide monotherapy in high-risk non-metastatic hormone-sensitive prostate cancer with rising PSA after local therapy: EMBARK study design

BMJ Open ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. e046588
Author(s):  
Stephen J Freedland ◽  
Ugo De Giorgi ◽  
Martin Gleave ◽  
Brad Rosbrook ◽  
Qi Shen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Specific Antigen ◽  
Local Therapy ◽  
Standard Of Care ◽  
Open Label ◽  
Phase 3 ◽  
Double Blind ◽  
Randomised Study ◽  
Definitive Therapy

IntroductionLimited data from controlled clinical trials are available for men who experience biochemical recurrence after definitive therapy for prostate cancer. In the absence of overt metastases, patients with non-metastatic castration-sensitive prostate cancer (nmCSPC) often receive androgen deprivation therapy (ADT). There is no standard-of-care consensus on optimal ADT timing, although most men are treated prior to metastases, especially those with high-risk features (Gleason score 8–10 or prostate-specific antigen doubling time (PSADT) <9–12 months). Given data that ADT plus novel hormonal agents improve survival in men with metastatic CSPC, there is a desire to evaluate these agents earlier in the disease course. The main objective of EMBARK is the comparative assessment of enzalutamide plus leuprolide (luteinising hormone-releasing hormone agonist (LHRHa)) or enzalutamide monotherapy versus monotherapy LHRHa to improve metastasis-free survival (MFS) in patients with high-risk nmCSPC PSA recurrence after definitive therapy.Methods and analysisEMBARK is a randomised, phase 3 study of high-risk patients with nmCSPC, a PSADT of ≤9 months and a screening PSA of ≥2 ng/mL above the nadir after radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) with or without postoperative RT. Men (n=1050) are randomised 1:1:1 to enzalutamide 160 mg/day plus LHRHa or placebo plus LHRHa (double-blind arms) or enzalutamide monotherapy (open-label arm). Treatment is suspended at week 37 if PSA concentrations are <0.2 ng/mL and reinstated if levels rise to ≥2.0 ng/mL with RP or ≥5.0 ng/mL without RP. Patients with PSA ≥0.2 ng/mL at week 37 continue until treatment discontinuation criteria are met. The primary endpoint is MFS comparing enzalutamide plus LHRHa versus placebo plus LHRHa.Ethics and disseminationThe study is conducted under the guiding principles of the World Medical Association Declaration of Helsinki. The results will be disseminated at research conferences and in peer-reviewed journals.Trial registration numberNCT02319837.

The effect of AKR1C3 on the switch from prednisone to dexamethasone in metastatic castration-resistant prostate cancer patients receiving abiraterone.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 133-133
Author(s):  
Yuchao Ni ◽  
Jinge Zhao ◽  
Junru Chen ◽  
Guangxi Sun ◽  
Sha Zhu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Free Survival ◽  
Castration Resistant ◽  
Kaplan Meier ◽  
Psa Progression ◽  
Biochemical Progression ◽  
First Line Treatment

133 Background: Abiraterone is the first-line treatment for men with metastatic castration-resistant prostate cancer (mCRPC) and is recommended to be used with prednisone. Previous studies had demonstrated that the switch from prednisone to dexamethasone in some mCRPC patients can reverse abiraterone-resistance. However, it remains uncertain which group of patients will benefit from such switching. AKR1C3 is a critical enzyme contributing to the drug-resistance of abiraterone. Here, we aim to explore the significance of AKR1C3 in predicting the therapeutic efficacy of the corticosteroid switching in mCRPC patients receiving abiraterone. Methods: In total, 43 PCa patients treated with abiraterone after mCRPC between 2016 and 2018 in our institution were included. After biochemical progression in abiraterone plus prednisone, all cases received a corticosteroid switch to abiraterone plus dexamethasone. The expression of AKR1C3 was detected by immunohistochemical staining from re-biopsy (re‐Bx) of primary prostate lesions at the time of mCRPC. Kaplan‐Meier curves were used to analyze the association between AKR1C3 and treatment outcomes. Results: Totally, AKR1C3 was positive in 19 of 43 (44.19%) cases. In the corticosteroid switch treatment, 30% PSA decline was confirmed in 18/43 (41.86%) patients, while the median PSA progression‐free survival (PSA-PFS) and overall survival (OS) was 4.93 Mo and 31.57 Mo, respectively in the whole cohort. AKR1C3 expression was associated with statistically shorter median PSA-PFS (4.50 Mo vs 7.73 Mo; p =0.010) and numerically lower median OS (25.43 Mo vs 39.37 Mo, p =0.274). While the 30% PSA decline rate was numerically comparable between those with and without AKR1C3 expression (31.6% vs 50.0%, p =0.224). Conclusions: This study showed AKR1C3 detection in tissues from prostate re‐Bx at mCRPC was associated with poor PSA-PFS in the corticosteroid switch from abiraterone plus prednisone to abiraterone plus dexamethasone. These results would be helpful in making optimal personalized treatment decisions for patients with mCRPC, facilitating physicians predicting the effectiveness of corticosteroid switch treatment.

scholarly journals Abiraterone versus bicalutamide in combination with gonadotropin releasing hormone antagonist therapy for high risk metastatic hormone sensitive prostate cancer.

2021 ◽  
Author(s):  
Takashi Ueda ◽  
Takumi Shiraishi ◽  
Saya Ueda ◽  
Motoharu Ohashi ◽  
Toru Matsugasumi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Progression Free Survival ◽  
Gonadotropin Releasing Hormone ◽  
Free Survival ◽  
Releasing Hormone ◽  
Group A ◽  
Psa Progression ◽  
Hormone Sensitive ◽  
Group B

Abstract ObjectivesTo compare the efficacy of abiraterone with that of bicalutamide in combination with gonadotropin-releasing hormone antagonist treatment for high risk metastatic hormone-sensitive prostate cancer patients.MethodsOne hundred and forty-nine patients with high risk metastatic hormone-sensitive prostate cancer at our hospital and affiliated hospitals between December 2013 and July 2020 were retrospectively identified. Fifty patients were administered abiraterone (1000mg/day) plus prednisolone (5mg/day) with gonadotropin-releasing hormone antagonist (degarelix) (group A) and 99 patients were administered bicalutamide (80mg/day) with gonadotropin-releasing hormone antagonist (group B). ResultsPSA- progression-free survival of group A was significantly longer than that of group B. Abiraterone therapy and Gleason score were significant independent factors for PSA-progression-free survival. By propensity score matching, total 56 matched patients were obtained. PSA-PFS (p<0.001) and OS (p=0.0071) of high risk mHNPC patients were significantly longer in abiraterone group of matched patients. Abiraterone therapy and Gleason score were still shown to be significant independent factors for PSA-PFS in matched patients.ConclusionsPSA-progression-free survival and overall survival in patients who were treated with abiraterone in combination with gonadotropin releasing hormone antagonist were significantly better than those of bicalutamide.

Clinical factors associated with AR-V7 detection in ARMOR3-SV, a randomized trial of galeterone (Gal) vs enzalutamide (Enz) in men with AR-V7+ metastatic castration-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5005-5005 ◽  
Author(s):  
Mary-Ellen Taplin ◽  
Emmanuel S. Antonarakis ◽  
Karen J. Ferrante ◽  
Kerry Horgan ◽  
Brent A. Blumenstein ◽  
...  
Keyword(s):  
Median Time ◽  
Primary Endpoint ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Free Survival ◽  
Castration Resistant ◽  
Treatment Naïve ◽  
Psa Progression ◽  
Study Designs

5005 Background: Presence of the AR-V7 splice variant may predict resistance to Enz and abiraterone in men with mCRPC. Gal is an oral agent that disrupts AR signaling via AR degradation, CYP17 lyase inhibition, and AR antagonism. ARMOR3-SV was designed to test the hypothesis that in mCRPC patients with AR-V7+ CTCs, Gal could improve radiographic progression-free survival (rPFS) versus Enz. Methods: In this randomized, open-label, multicenter phase 3 study (NCT02438007), men with treatment-naïve mCRPC were screened for CTC-specific AR-V7 (Qiagen), and AR-V7+ men were randomized 1:1 to Gal or Enz. rPFS (by independent blinded central review) was the primary endpoint. Planned sample size was 148, with 120 rPFS events to achieve 90% power to detect a hazard ratio of ≤0.55. Results: 953 patients were screened globally for AR-V7 from Sept 2015 through study closure; 73 men (8%; 95% CI 6-10%) were AR-V7+, 250 (26%) AR-V7–, and 630 (66%) had no CTCs/AR present (unevaluable). AR-V7 detection was associated with higher PSA levels ( > vs < median; P < 0.01), more bone metastases ( > 20 vs 11-20 vs 6-10 vs 0-5; P < 0.01), presence of M1 disease at diagnosis (dx) (yes vs no; P = 0.04), shorter time from dx to screening ( < vs > median; P < 0.01), higher ECOG (≥1 vs 0; P = 0.02), prior antiandrogen use (yes vs no; P < 0.01) and prior docetaxel use (yes vs no; P < 0.01). Among the AR-V7+ men, 38 were randomized (19 Gal, 19 Enz), 31 screen failed, and 4 were discontinued from screening at study halt. Baseline characteristics were balanced. On the recommendation of the DSMB, the study was closed early as it was unlikely to meet its primary endpoint. At the time of the study closure, in the Gal and Enz arms respectively, median time on therapy was 2.0 vs 2.8 mo, median time to PSA progression (PCWG1) was 3.9 vs 3.8 mo, PSA50 response rates in evaluable patients were 2/16 (13%) and 8/19 (42%), and there were no new safety signals. Conclusions: In treatment-naïve mCRPC patients, AR-V7 detection is more common in men with higher disease burden and portends a poor prognosis. Novel study designs and alternative treatment approaches are urgently needed for AR-V7+ mCRPC patients. Clinical trial information: NCT02438007.

The value of AKR1C3 in predicting the therapeutic efficacy of abiraterone for patients with metastatic castration-resistant prostate cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 313-313
Author(s):  
Jinge Zhao
Keyword(s):  
Prostate Cancer ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
Androgen Synthesis ◽  
Castration Resistant ◽  
Psa Progression ◽  
The Difference

313 Background: AKR1C3 is a multifunctional enzyme playing a significant role in androgen synthesis and metabolism. Previous studies have proved that the activation of AKR1C3 was associated with resistance to abiraterone through increasing the intracrine androgen synthesis. However, clinical validation is still lacking as to the prognostic value of AKR1C3 in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone. Methods: Data of 117 patients with mCRPC between 2016-2018 in our center were retrospectively analyzed. AKR1C3 was detected by the immunohistochemical staining from the 12-core prostate biopsy. Kaplan-Meier curves and COX regression were used to analyze the association between AKR1C3 and the treatment outcomes of abiraterone. The endpoints of this study were PSA progression-free survival (PSA-PFS) and radiograph progression-free survival (rPFS). Results: In total, AKR1V3 was detected in 40/117 (34.2%) cases. The positive AKR1C3 was significantly associated with shorter PSA-PFS for mCRPC patients treated with abiraterone (median PSA-PFS: 6.2 Mo vs. 11.1 Mo, p < 0.001). Those with positive AKR1C3 were also accompanied with obviously poorer rPFS compared to those with negative AKR1C3 staining, despite that the difference was not statistically significant (median rPFS: 11.1 Mo vs. 21.8 Mo, p = 0.250). Multivariate COX regression indicated that, AKR1C3 was an independent prognosticator of rapid PSA progression for the abiraterone treatment (HR,95%CI: 2.612, 1.54-4.44, p < 0.001). Conclusions: This is the first study verifying the adverse prognostic significance of AKR1C3 for mCRPC patients receiving abiraterone treatment. Our results suggested that, AKR1C3 was closely related to early treatment failure of abiraterone, and thus, was worthwhile to be routinely described in pathological report.

scholarly journals Consecutive Prostate Cancer Specimens Revealed Increased Aldo–Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer

2019 ◽  
Vol 8 (5) ◽  
pp. 601 ◽  
Author(s):  
Yu Miyazaki ◽  
Yuki Teramoto ◽  
Shinsuke Shibuya ◽  
Takayuki Goto ◽  
Kosuke Okasho ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Immunohistochemical Expression ◽  
Free Survival ◽  
Castration Resistant ◽  
Psa Progression ◽  
Prostatic Epithelium

Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to understand the role of AKR1C3 in PCa progression. Correlation of AKR1C3 immunohistochemical expression between benign and cancerous epithelia in 134 patient specimens was analyzed. Additionally, correlation between AKR1C3 expression and prostate-specific antigen (PSA) progression-free survival (PFS) after radical prostatectomy was analyzed. Furthermore, we evaluated the consecutive prostate samples derived from 11 patients both in the hormone-naïve and castration-resistant states. AKR1C3 immunostaining of cancer epithelium was significantly stronger than that of the benign epithelia in patients with localized HNPC (p < 0.0001). High AKR1C3 expression was an independent factor of poor PSA PFS (p = 0.032). Moreover, AKR1C3 immunostaining was significantly stronger in CRPC tissues than in HNPC tissues in the same patients (p = 0.0234). Our findings demonstrate that AKR1C3 is crucial in PCa progression.

scholarly journals Abiraterone Alone or in Combination With Enzalutamide in Metastatic Castration-Resistant Prostate Cancer With Rising Prostate-Specific Antigen During Enzalutamide Treatment

2018 ◽  
Vol 36 (25) ◽  
pp. 2639-2646 ◽  
Author(s):  
Gerhardt Attard ◽  
Michael Borre ◽  
Howard Gurney ◽  
Yohann Loriot ◽  
Corina Andresen-Daniil ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Control Group ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
Castration Resistant ◽  
Psa Progression

Purpose Enzalutamide resistance could result from raised androgens and be overcome by combination with abiraterone acetate. PLATO ( ClinicalTrials.gov identifier: NCT01995513) interrogated this hypothesis using a randomized, double-blind, placebo-controlled design. Patients and Methods In period one, men with chemotherapy-naïve metastatic castration-resistant prostate cancer received open-label enzalutamide 160 mg daily. Men with no prostate-specific antigen (PSA) increase at weeks 13 and 21 were treated until PSA progression (≥ 25% increase and ≥ 2 ng/mL above nadir), then randomly assigned at a one-to-one ratio in period two to abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily with either enzalutamide or placebo (combination or control group, respectively) until disease progression as defined by the primary end point: progression-free survival (radiographic or unequivocal clinical progression or death during study). Secondary end points included time to PSA progression and PSA response in period two. Results Of 509 patients enrolled in period one, 251 were randomly assigned in period two. Median progression-free survival was 5.7 months in the combination group and 5.6 months in the control group (hazard ratio, 0.83; 95% CI, 0.61 to 1.12; P = .22). There was no difference in the secondary end points. Grade 3 hypertension (10% v 2%) and increased ALT (6% v 2%) or AST (2% v 0%) were more frequent in the combination than the control group. Conclusion Combining enzalutamide with abiraterone acetate and prednisone is not indicated after PSA progression during treatment with enzalutamide alone; hypertension and elevated liver enzymes are more frequent with combination therapy.

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