1836P - Blood based biomarkers identify metastatic castration-resistant prostate cancer (mCRPC) with the greatest benefit from continuing enzalutamide (ENZ) beyond progression in combination with docetaxel (Doc): A pre-specified biomarker study of the phase IIIb PRESIDE trial

Background

PRESIDE (NCT02288247) was a randomised, international trial that met its primary endpoint of prolonged progression-free survival (PFS) with continued ENZ beyond progression in patients (pt) starting Doc. A pre-specified aim of PRESIDE was to test for androgen receptor (AR) blood-based biomarkers to test for differential benefit.

Methods

Pt who participated in PRESIDE, consented to the biomarker sub-study and donated blood at randomization (Period 2 baseline, P2BL) were included. Blood was also collected on treatment (P2 Week [W] 4 and 13), progression and follow up. Pre-specified primary objectives were to evaluate PFS for 1) ENZ versus (v) Placebo (P) in pt split by +/- plasma AR gain or AR-V7 in circulating tumor cells (CTC) at P2BL and 2) PFS for all pt split by +/- tumor in plasma DNA (ptDNA) at P2W4. Custom targeted next-generation sequencing on plasma DNA was performed using a bespoke panel (PCF SELECT). Identification of CTC +/- AR-V7 in whole blood samples was performed by Epic Sciences (San Diego, California).

Results

Of 271 pt randomised to ENZ / P, 157 (57.9%, 79 on ENZ + Doc, 78 on P + Doc) donated blood. 100 (64%) were plasma AR wild type (wt), 56 (36%) had AR gain. 126 (80%) were AR-V7 negative (-), 17 (11%) AR-V7 positive (+). AR status not available for plasma DNA (1 pt) and CTC (14 pt, 9%). Pt who were AR wt and AR-V7- (N=87, 55%) had significantly prolonged PFS from continuing ENZ (11.2 months (m) v 8.7 m P, HR: 0.49; 95% CI: 0.29-0.82, p=0.006), whilst pt with AR gain or AR-V7+ (N=62) did not (6.2 m ENZ v 7.9 m P; HR: 1.29; p=0.44). Restricted mean survival times at 18 m for AR wt and AR-V7- was 11.5 m ENZ v 8.9 m P, p=0.0046, for AR gain or AR-V7 + was 7.9 m ENZ vs 7.1 m P, p=0.5023. Compared with negative ptDNA at P2W4 (99, 74% of 134 pt included), pt with positive ptDNA (35, 26%) had significantly shorter PFS (5.4 m vs 10.8 m, HR: 1.92; 95% CI: 1.14-3.23, p=0.0145).

Conclusions

The benefit of continuing ENZ beyond progression with Doc vs Doc alone is greatest in patient with no evidence of plasma AR gain or AR-V7+ CTC. Plasma tumor DNA detection after 3 weeks Doc +/- ENZ identifies patients with shorter PFS.

Clinical trial identification

NCT02288247.

Editorial acknowledgement

Legal entity responsible for the study

Prof. Gerhardt Attard (Principal Investigator), Head of Treatment Resistance Group, University College London.

Funding

Academic group (UCL) with funding from Astellas, CRUK (Cancer Research United Kingdom) and SEOM (Spanish Society of Medical Oncology).

Disclosure

M. Ruiz Vico: Financial Interests, Institutional, Research Grant: Astellas Pharma Europe Ltd; Financial Interests, Personal, Research Grant, 2-year FSEOM grant for training in translational research in reference centres abroad. Spanish Society of Medical Oncology (SEOM). Awarded in 2018: Spanish Soctiey of Medical Oncology (SEOM); Non-Financial Interests, Project Lead: Astellas Pharma Europe Ltd. D.E. Castellano Gauna: Financial Interests, Personal, Advisory Board: Pfizer, Roche, BMS, Janssen, Astellas, MSD, Ipsen, AstraZeneca Novartis, GSK; Financial Interests, Institutional, Local PI: Pfizer, Roche, MSD, BMS, AstraZeneca Janssen, Astellas, Ipsen, Exelisis, Eisai, Lilly, Bayer, GSK, Clovis, QED Therapeutics; Non-Financial Interests, Personal, Other, Executive member: SOGUG (Spanish Oncology Genito-Urinary Group) Foundation. K.D. Martins, G. Gourgioti, A. Serikoff: Financial Interests, Personal, Full or part-time Employment: Astellas Europe Pharma Ltd.. K. Iwata: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma USA. L. Astrom: Financial Interests, Personal, Financially compensated role: Merck Sharpe & Dohme, Pfizer, Merck, Janssen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Merck Sharpe & Dohme. V. Matveev: Financial Interests, Personal, Financially compensated role: Astellas Pharma. S. Feyerabend: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Bayer, Aventis; Financial Interests, Personal, Financially compensated role: Janssen; Financial Interests, Personal, Other, Travel expenses and accommodation: Aventis. E. Senkus-Konefka: Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca, Cancérodigest, Eli Lilly, Gilead, high5md, Novartis, Pfizer, MSD; Financial Interests, Personal, Writing Engagement: AstraZeneca; Financial Interests, Personal, Other, commenting on scientific meeting in social media: Curio Science; Financial Interests, Personal, Other, travel expenses: Gilead, Egis, Novartis, Roche; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Eli Lilly, Pfizer; Financial Interests, Personal, Royalties: Springer; Financial Interests, Personal and Institutional, Local PI: Amgen, Eli Lilly, Novartis, OBI Pharma, Samsung; Financial Interests, Personal and Institutional, Other, SI: AstraZeneca, Roche, Pfizer. S. Gupta: Financial Interests, Personal, Full or part-time Employment, Employee: Epic Sciences. A.S. Merseburger: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Astellas, Bayer, BMS, Eisai, Ferring, Ipsen, MSD, Merck Serono, Janssen, Takeda, TEVA, Novartis, Pfizer, Recordati, Roche, EUSAPharm; Financial Interests, Personal and Institutional, Research Funding: AstraZeneca, Astellas, Bayer, BMS, Ipsen, Janssen, EUSAPharm, MSD, Merck Serono, Novartis, Pfizer, Takeda, TEVA, Roche. G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion, Novartis; Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone: Institute of Cancer Research; Financial Interests, Institutional, Advisory Board: Artera, Veracyte; Financial Interests, Institutional, Research Grant: Janssen, Astellas, Novartis; Financial Interests, Institutional, Coordinating PI: Janssen; Financial Interests, Institutional, Local PI: Novartis, Pfizer; Non-Financial Interests, Principal Investigator: Janssen, Astellas; Non-Financial Interests, Advisory Role: Janssen, AstraZeneca; Non-Financial Interests, Project Lead: Artera, Veracyte. All other authors have declared no conflicts of interest.