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.

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.

A phase III, randomized, open-label, study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy (NHT) in patients (pts) with metastatic, castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS190-TPS190
Author(s):  
Neeraj Agarwal ◽  
Arun Azad ◽  
Joan Carles ◽  
Simon Chowdhury ◽  
Bradley Alexander McGregor ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Soft Tissue ◽  
Objective Response ◽  
Specific Antigen ◽  
Phase Iii ◽  
Disease Stage ◽  
Open Label ◽  
Phase 3 ◽  
Recist 1.1 ◽  
Cancer Aggressiveness

TPS190 Background: Cabozantinib inhibits multiple tyrosine kinases, including MET, VEGFR, RET, and TAM kinases (Tyro3, AXL, MER), involved in tumor growth and angiogenesis, and whose mutations and expression are associated with prostate cancer aggressiveness and poor prognosis. Targeting these kinases with cabozantinib may promote an immune permissive tumor environment and may enhance response to immune checkpoint inhibitors. In the ongoing phase 1b COSMIC-021 study of pts with solid tumors, cabozantinib plus the PD-L1 inhibitor atezolizumab, showed preliminary meaningful clinical activity in soft tissue disease and a tolerable safety profile for 44 pts with mCRPC (Agarwal et al., ASCO 2020; abstract 5564). We present the study design of a phase 3 trial of cabozantinib plus atezolizumab versus second NHT in pts with mCRPC. Methods: This randomized, open-label, controlled phase 3 study (NCT04446117) evaluates the efficacy and safety of cabozantinib plus atezolizumab versus second NHT (abiraterone or enzalutamide) in pts with mCRPC who previously received one NHT to treat metastatic castration-sensitive PC (mCSPC), non-metastatic CRPC (M0 CRPC), or mCRPC. Additional eligibility criteria include histologically or cytologically confirmed adenocarcinoma of the prostate, measurable visceral disease or measurable extrapelvic adenopathy per RECIST 1.1 by investigator, prostate specific antigen progression and/or soft-tissue disease progression, ECOG 0 or 1, and age ≥18 years. Key exclusion criteria include prior nonhormonal therapy for mCRPC and uncontrolled significant illness. Eligible pts (N = 580) are randomized 1:1 to receive cabozantinib (40 mg PO QD) + atezolizumab (1200 mg IV Q3W) vs abiraterone (1000 mg PO QD) + prednisone (5 mg PO BID) or enzalutamide (160 mg PO QD). Designated NHT will differ from previous NHT taken. Randomization is stratified by: liver metastasis (yes, no), prior docetaxel treatment for mCSPC (yes, no), and disease stage for which the first NHT was given (mCSPC, M0 CRPC, mCRPC). Treatment will continue until there is no longer clinical benefit as determined by the treating investigator, unacceptable toxicity, or consent withdrawal. The multiple primary endpoints are progression-free survival per RECIST 1.1 by blinded independent radiology committee (BIRC) and overall survival. Additional endpoints include objective response rate per RECIST 1.1 by BIRC, safety, correlation of biomarkers with outcomes, quality of life and pharmacokinetics. Patient enrollment is ongoing. Clinical trial information: NCT04446117.

A phase Ib/II, open-label, platform study evaluating the efficacy and safety of AB928-based treatment combinations in participants with metastatic castrate-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS272-TPS272
Author(s):  
David R. Wise ◽  
Olivia Gardner ◽  
Houston N. Gilbert ◽  
Aimee Rieger ◽  
Melissa Constance Paoloni ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Molecule ◽  
Single Agent ◽  
Specific Antigen ◽  
Standard Of Care ◽  
The United States ◽  
Experimental Therapy ◽  
Efficacy And Safety ◽  
Open Label ◽  
Castrate Resistant

TPS272 Background: The tumor microenvironment contains high levels of immunosuppressive adenosine, which binds to and activates the A2a and A2b receptors (R) on immune cells, resulting in an ineffective anti-tumor immune response. Extracellular adenosine is primarily produced by the enzyme CD73. In prostate cancer (PC), the activity of prostatic acid phosphatase produces additional adenosine. AB928 is the first clinical-stage small molecule dual antagonist of both A2aR and A2bR, which is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Targeting the adenosine pathway in combination with standard of care regimens may have a more profound effect on activating and inducing sustained anti-tumor immunity. Methods: This Phase 1b/2, open-label, multi-cohort platform study will evaluate the efficacy and safety of AB928 combination therapy in participants with metastatic castrate resistant PC (mCRPC). Each cohort will independently assess AB928 plus AB122 (anti-PD-1 antibody) in combination with standard of care (SOC; enzalutamide, docetaxel) or AB928 plus AB680 (CD73 inhibitor) with or without AB122. Cohort eligibility is informed by prior treatment history. In Ph1b, up to 15 participants will receive investigational products at the single-agent recommended dose with SOC per label guidance. Provided safety and activity stopping criteria are not met, further accrual will proceed in Ph2 and, depending on treatment cohort, may involve randomization to enzalutamide or docetaxel; crossover to experimental therapy will be allowed following progression on control treatment. Investigator-assessed antitumor response (radiologic, prostate specific antigen) will follow PCWG3 criteria. Conclusions: This Ph1b/2 study is the first to target the adenosine axis using a dual A2aR/A2bR antagonist (AB928) together with a small molecule CD73 inhibitor (AB680), anti-PD-1 antibody (AB122), and SOC for mCRPC. Study enrollment is proceeding in the United States; results will be shared in upcoming scientific conferences.

Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 533-533
Author(s):  
Douglas W. Blayney ◽  
Yuankai Shi ◽  
Hryhorii Adamchuk ◽  
David Feng ◽  
Qingyuan Zhang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Safety Profile ◽  
Early Stage ◽  
Standard Of Care ◽  
Primary Objective ◽  
Severe Neutropenia ◽  
Double Blind Study ◽  
Phase 3 ◽  
Double Blind

533 Background: Peg is standard of care (SoC) for the prevention of CIN. Peg’s mechanism of action leaves patients vulnerable to FN in week 1 of the chemo cycle(C), as the absolute neutrophil count (ANC) does not normalize until week 2. Plin is a first-in-class, non-G-CSF small molecule agent, which received breakthrough designation from FDA in CIN. It prevents CIN by protecting progenitor cells in bone marrow from chemo assault and has normal ANC in week 1 (Blayney JAMA Onc 2020). Phase 2 testing showed the combination of Plin and Peg achieved CIN protection throughout the entire cycle vs Peg alone (Blayney: St Gallen 2019, ASCO 2019). Methods: Plin is given on Day (D)1 after Chemo, has a favorable safety profile, and also has anticancer activity. A separate phase 3 study evaluating Plin as an anticancer agent (DUBLIN-3; NCT02504489) in NSCLC pts is underway, with anti-cancer results in OS expected in 2021. In PROTECTIVE-2 (Study 106; NCT0329457), we added Plin (on D1) to Peg (on D2), testing superiority of the combination for CIN prevention vs Peg alone. Study 106, is a global multicenter randomized (1:1) double-blind study to evaluate Plin 40 mg + Peg 6mg (Arm 1) versus Peg 6mg + Placebo (Plac) (Arm 2) in preventing Severe Neutropenia (N), (defined as ANC <0.5 cells × 10E9/L) in early-stage BC (node positive or node negative with a high risk of recurrence) pts. 221 pts with ECOG status 0 or 1 received Docetaxel (75 mg/m2), Doxorubicin (50 mg/m2), and Cyclophosphamide (500 mg/m2) (TAC) on D1 for four 21 D cycles and study treatment. Central laboratory ANC was assessed at Covance in Cycle 1 (C1) on D 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, and 15. Primary objective was to compare the percentage (%) of pts with a Duration of Severe Neutropenia (DSN) of 0 days [that is % of pts with no Grade (Gr) 4 neutropenia (N)] in C1 in each arm. Key secondary endpoints were DSN and ANC Nadir in C1. We also evaluated safety (AE frequency and Grade). Conclusions: Adding Plin to Peg offers superior CIN protection compared to Peg alone and also has a superior safety profile by lowering over 20% of grade 4 AE. The effect size of the CIN protection in the combination is also correlated to clinical meaningful FN reduction compared to peg alone. Clinical trial information: NCT03531099. [Table: see text]

The ELDORADO study: A phase II randomised study of concurrent weekly docetaxel, IMRT, and ltadt in patients with high-risk prostate cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5048-5048
Author(s):  
Derek Wilke ◽  
Lori Wood ◽  
Heather Walker ◽  
David Bell ◽  
Ricardo A. Rendon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Treatment Intensification ◽  
Double Blind ◽  
Randomised Study ◽  
High Risk Prostate Cancer ◽  
Gu Toxicity ◽  
Risk Prostate Cancer ◽  
Grade 3 ◽  
Dose Reductions

5048 Background: Treatment intensification is warranted for ‘high risk’ prostate cancer. Docetaxel (DO) and radiotherapy (IMRT) may cause dose-limiting GI or GU toxicity. Treating the whole pelvis last (WP-L) versus the whole pelvic lymphatics first (WP-F) could reduce the number of dose delays or omissions of DO. Methods: We performed a double-blind, randomized trial, in patients with ‘high risk’ non-metastatic prostate cancer who had any one of the following: 1) ≥ T2c TNM category, 2) Gleason score ≥ 8, or PSA > 20 and < 50 µg/L, OR have a greater than 50% risk of recurrence after radical prostatectomy (RP), as predicted by the Kattan nomogram, with no evidence of metastatic disease. Patients receive long-term androgen deprivation therapy (LTADT), and after 4 months of neoadjuvant ADT, receive IMRT and concurrent DO 20 mg/m2 x 8 weekly infusions. Patients were randomized to receive WP-F followed by a boost to the prostate/prostate bed, or to have WP-L. The primary outcome was to compare the number of DO dose reductions, delays or omissions due to GI or GU toxicity, between arms. Target sample size was 86 patients (pts). Results: 98 pts were registered, 88 were randomized, 2 withdrew consent, leaving 42 pts randomized to WP-F, and 44 pts to WP-L. The trial was closed to accrual Feb 2, 2012. Twenty-five pts had previous RP (29%). Seven pts (16.6%) allocated to WP-F had chemotherapy dose reductions/delays versus 3 pts (6.8%) allocated to WP-L , which was not statistically significant (p=0.19). Overall 80.2% of pts received all 8 weekly doses of DO and IMRT (WP-F vs. WP-L: 78.6% vs.81.8%, p=0.9). Actuarial overall survival at 4 years is 96 % (WP-F vs. WP-L: 94% vs.97%, p=0.6). Biochemical relapse-free survival at 4 years is 96.7% (WP-F vs. WP-L: 98% vs.97%, p=0.92). Two patients have needed surgical intervention for Grade > 3 GU toxicity. Cumulative treatment-related grade 3 or 4 GI or GU toxicity was 36%. When patients were last seen, only 2/84 (2.3%) patients had ongoing grade 3 GI or GU toxicity at a median follow up of 2.7 years Conclusions: Concurrent use of DO and IMRT is feasible with reasonable toxicity. Sequence inversion does not enhance chemotherapy delivery. Clinical trial information: NCT00452556.

PROTEUS: A randomized, double-blind, placebo (PBO)-controlled, phase 3 trial of apalutamide (APA) plus androgen deprivation therapy (ADT) versus PBO plus ADT prior to radical prostatectomy (RP) in patients with localized high-risk or locally advanced prostate cancer (PC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5100-TPS5100 ◽  
Author(s):  
Mary-Ellen Taplin ◽  
Martin Gleave ◽  
Christopher P. Evans ◽  
Eleni Efstathiou ◽  
Philip W. Kantoff ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Specific Antigen ◽  
Data Monitoring Committee ◽  
Eligibility Criteria ◽  
Double Blind ◽  
End Points ◽  
Free Survival

TPS5100 Background: Patients (pts) with localized high-risk PC experience disease progression rates of approximately 50% after RP (Kane et al. J Urol. 2007). With the approval of next-generation androgen receptor inhibitors, neoadjuvant studies have shown that 6 months of androgen blockade may improve local disease control at the time of RP (McKay et al. Prostate Cancer Prostatic Dis. 2017; Taplin et al. JCO. 2014). The purpose of this study is to determine if treatment with APA plus ADT before and after RP in pts with localized high-risk or locally advanced PC results in an improvement in pathologic complete response (pCR) rate and metastasis-free survival (MFS) compared with PBO plus ADT. Methods: This international multicenter trial is enrolling pts with localized high-risk or locally advanced PC who are candidates for RP. Eligibility criteria: Any Gleason score (GS) ≥ 4 + 3 with ≥ 6 positive systematic biopsies (SB); any GS ≥ 4 + 3 with ≥ 3 SB and prostate-specific antigen (PSA) ≥ 20 ng/mL; GS ≥ 9 in ≥ 1 SB or targeted biopsies (TB); or ≥ 2 SB or TB with continuous GS ≥ 8, each with ≥ 80% involvement. Stratification: GS (7 or ≥ 8), cN0 or N1, and region (North America, Europe, or rest of world). Randomization: 1:1 to APA (240 mg) plus ADT (LHRHa) or PBO plus ADT. Pts will receive 6 treatment cycles, followed by RP, followed by an additional 6 cycles. Dual primary end points: pCR rate (to be assessed by blinded independent central pathology review) and MFS (to be assessed by blinded independent central radiology review [BICR]). Secondary end points: PSA-free survival and progression-free survival. Imaging with CT or MRI and bone scan will be conducted at baseline and then every 6 months following biochemical failure until documented distant metastasis by BICR, or death. Approximately 1500 pts will be enrolled globally over 3.0 years in 240 sites in 19 countries. An independent data monitoring committee is commissioned to review trial data. Clinical trial information: NCT03767244.

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