Background

C may enhance response to immune checkpoint inhibitors by promoting an immune-permissive microenvironment. COSMIC-021 (NCT03170960), a multinational phase 1b study, is evaluating C + A in solid tumors, including mCRPC, which has limited treatment options after failure of novel hormonal therapy (NHT). We report efficacy and safety results of expanded cohort 6 in mCRPC.

Methods

Eligible pts had measurable disease, radiographic progression in soft tissue after enzalutamide and/or abiraterone, and ECOG PS of 0 or 1. Prior chemotherapy for metastatic castration-sensitive prostate cancer (mCSPC) was permitted. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for 52W and Q12W thereafter. The primary endpoint was ORR by investigator (INV) per RECIST 1.1. Other endpoints included safety, PFS, and OS.

Results

As of the data cutoff of 19 Feb 2021, 132 mCRPC pts were enrolled with a median (range) follow-up of 15.2 mo (5.7, 33.9). Median age was 70 y, 68 (52%) had ECOG PS 0, and 101 (77%) had measurable visceral metastases (mets) and/or extrapelvic lymphadenopathy (EPLN); 42 (32%) had visceral mets and 79 (60%) had EPLN; 33 (25%) had prior docetaxel for mCSPC, and 59 (45%) had received ≥2 prior NHT. Frequent treatment-related adverse events (TRAEs) were diarrhea (55%), nausea (42%), fatigue (43%) and decreased appetite (34%). Grade 3/4 TRAEs occurred in 55%; one grade 5 TRAE of dehydration was reported in a 90 y/o. ORR by INV among all pts per RECIST 1.1 was 23% with 3 CRs; ORR by independent review (BIRC) was 15% (all PRs); DCR (CR + PR + SD) was 84% by INV and 81% by BIRC. In pts with visceral mets and/or EPLN, ORR by INV was 27% with 2 CRs and 18% by BIRC (all PRs); DCR was 88% by INV and 84% by BIRC. Median PFS per RECIST 1.1 by BIRC was 5.7 mo in all pts and 6.8 mo in pts with visceral mets and/or EPLN; median OS was 18.4 mo in both groups. Preliminary data do not suggest an association between tumor PD-L1 status (known for 75 pts) and anti-tumor activity.

Conclusions

C + A demonstrated clinically meaningful activity with a manageable safety profile in mCRPC, supporting a phase 3 study of C + A versus second NHT (CONTACT-02; NCT04446117).

Clinical trial identification

XL184-021; NCT03170960.

Editorial acknowledgement

Medical writing assistance provided by Julie Lougheed, PhD (Exelixis, Inc.).

Legal entity responsible for the study

Exelixis.

Funding

Exelixis.

Disclosure

N. Agarwal: Financial Interests, Personal, Other, Advisory Board, Honoraria: Astellas; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Advisory Board, Honoraria: AstraZeneca; Financial Interests, Institutional, Research Grant: Bavarian Nordic; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Personal, Other, Advisory Board, Honoraria: Bayer; Financial Interests, Institutional, Research Grant: BN immunotherapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Other, Advisory Board, Honoraria: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Calithera; Financial Interests, Institutional, Other, Advisory Board, Honoraria: Calithera; Financial Interests, Research Grant: Celldex; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Personal, Other, Advisory Board, Honoraria: Clovis; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Personal, Other, Advisory Board, Honoraria: Eisai; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Personal, Other, Advisory Board, Honoraria: Eli Lilly; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Personal, Other, Advisory Board, Honoraria: EMD Serono; Financial Interests, Institutional, Research Grant: Exelixis; Financial Interests, Personal, Other, Advisory Board, Honoraria: Exelixis; Financial Interests, Personal, Other, Advisory Board, Honoraria: Foundation Medicine; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Personal, Other, Advisory Board, Honoraria: Genentech; Financial Interests, Institutional, Research Grant: Glaxo Smith Kline; Financial Interests, Institutional, Research Grant: Immunomedics; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Personal, Other, Advisory Board, Honoraria: Janssen; Financial Interests, Institutional, Research Grant: Medivation; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Personal, Other, Advisory Board, Honoraria: Merck; Financial Interests, Institutional, Research Grant: Nektar; Financial Interests, Personal, Other, Advisory Board, Honoraria: Nektar; Financial Interests, Institutional, Research Grant: New Link Genetics; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Other, Advisory Board, Honoraria: Novartis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Personal, Other, Advisory Board, Honoraria: Pfizer; Financial Interests, Personal, Other, Advisory Board, Honoraria: Pharmacyclics; Financial Interests, Institutional, Research Grant: Prometheus; Financial Interests, Institutional, Research Grant: Rexahn; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Seattle Genetics; Financial Interests, Personal, Other, Advisory Board, Honoraria: Seattle Genetics; Financial Interests, Institutional, Research Grant: Takeda; Financial Interests, Institutional, Research Grant: Tracon; Financial Interests, Personal, Other, Advisory Board, Honoraria: Aveo; Financial Interests, Personal, Other, Advisory Board, Honoraria: MEI Pharma. B.A. McGregor: Financial Interests, Personal, Advisory Role: Pfizer, Exelixis, Astellas, Seattle Genetics, EMD Serono, Eisai, Dendreon, BMS, Calithera; Financial Interests, Personal and Institutional, Sponsor/Funding: Exelixis, BMS, Seattle Genetics, Calithera, Pfizer. B.L. Maughan: Financial Interests, Personal, Advisory Role: AVEO oncology, Janssen, Astellas, Bristol Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology and Peloton Therapeutics; Financial Interests, Institutional, Research Grant: Exelixis, Bavarian-Nordic, Clovis, Genentech and Bristol Myers Squibb. T. Dorff: Financial Interests, Personal, Advisory Role: AstraZeneca; Bayer; Bristol Myers Squibb; Janssen Oncology; Noxopharm; Roche; Seattle Genetics; Financial Interests, Personal, Speaker’s Bureau: Exelixis; Prometheus; Financial Interests, Personal and Institutional, Research Grant: Bayer; Bristol Myers Squibb. B. Fang: Financial Interests, Institutional, Full or part-time Employment: NYU School of Medicine; Financial Interests, Personal, Full or part-time Employment: Regional Cancer Care Associates; Financial Interests, Personal, Stocks/Shares: Regional Cancer Care Associates. R. McKay: Financial Interests, Personal, Advisory Role: AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Dendreon, Exelixis, Janssen, Merck, Novartis, Pfizer, Sanofi, and Tempus; Financial Interests, Personal, Advisory Role: Myovant, Vividion; Financial Interests, Personal, Other, Honoraria: Bayer, BMS, Exelixis, Merck; Financial Interests, Personal, Research Grant: Pfizer, Tempus, Bayer; Financial Interests, Personal, Other, Molecular tumor board member: Caris. P. Singh: Financial Interests, Personal, Advisory Role: EMD soreno. R. Dreicer: Financial Interests, Personal, Advisory Role: Astellas, Bayer, Exelixis, EMD Serono Gilead, Hinova, Infinity, Janssen, Merck, Myovant, Pfizer, Propella, Tavanta, Veru; Financial Interests, Personal, Funding: BMS, Seagen, Arvinas. S. Srinivas: Financial Interests, Personal, Advisory Role: Genentech/Roche; Financial Interests, Personal, Speaker’s Bureau: Genentech; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb (Inst); Exelixis (Inst); Genentech (Inst); Merck . Y. Loriot: Financial Interests, Personal and Institutional, Advisory Role: Astellas Pharma; AstraZeneca; Bristol Myers Squibb; Clovis Oncology; Janssen; Janssen (Inst); MSD Oncology; MSD Oncology (Inst); Roche; Seattle Genetics; Financial Interests, Institutional, Funding: AstraZeneca (Inst); Boehringer Ingelheim (Inst); Clovis Oncology (Inst); CureVac (Inst); Exelixis (Inst); Incyte (Inst); Janssen Oncology (Inst); Medivation (Inst); MSD Oncology (Inst); Nektar (Inst); Oncogenex (Inst); Pfizer (Inst); Sanofi (Inst); Financial Interests, Personal, Other, Travel, Accommodations, and/or Expenses: Astellas Pharma; AstraZeneca; Janssen Oncology; MSD Oncology; Roche; Seattle Genetics. U.N. Vaishampayan: Financial Interests, Personal, Advisory Role: Exelixis, Merck, BMS, Bayer; Financial Interests, Personal, Other, Honoraria: Exelixis, Bayer, Merck, BMS; Financial Interests, Personal and Institutional, Research Grant: BMS, Merck, Astellas. S. Goel: Financial Interests, Institutional, Research Grant: BeiGene (Inst); Oncolytics (Inst); Financial Interests, Personal, Other, a patent with a co-inventor, John Mariadason, Ph.D, entitled: See notes. D. Curran: Financial Interests, Personal, Full or part-time Employment: Exelixis, Inc.; Financial Interests, Personal, Stocks/Shares: Exelixis, Inc. A. Panneerselvam: Financial Interests, Personal, Full or part-time Employment: Exelixis, Inc.; Financial Interests, Personal, Stocks/Shares: Exelixis, Inc. L. Liu: Financial Interests, Personal, Full or part-time Employment: Exelixis, Inc.; Financial Interests, Personal, Stocks/Shares: Exelixis, Inc. T.K. Choueiri: Financial Interests, Personal, Full or part-time Employment: - Dana Farber Cancer Hospital; Financial Interests, Personal, Leadership Role: ASCO; Dana Farber Cancer Hospital; KidneyCan; NCCN; Financial Interests, Personal, Other, Honoraria: Alexion Pharmaceuticals; alligent; Analysis Group; ASCO; AstraZeneca; Bayer; Bristol Myers Squibb; Cerulean Pharma; Clinical Care Options; Corvus Pharmaceuticals; Eisai; EMD Serono; Exelixis; Foundation Medicine; Genentech/Roche; GlaxoSmithKline; Harborsi; Financial Interests, Personal, Advisory Role: Alexion Pharmaceuticals; alligent; Analysis Group; ASCO; AstraZeneca; Bayer; Bristol Myers Squibb; Cerulean Pharma; Clinical Care Options; Corvus Pharmaceuticals; Eisai; EMD Serono; ESMO; Exelixis; Foundation Medicine; GlaxoSmithKline; Harborside Press; H; Financial Interests, Institutional, Funding: - Agensys (Inst); Analysis Group (Inst); AstraZeneca (Inst); Bayer (Inst); Bristol Myers Squibb (Inst); Calithera Biosciences (Inst); Celldex (Inst); Cerulean Pharma (Inst); Congressionally Directed Medical Research Programs (DOD) (Inst); Corvus Pharmaceu; Financial Interests, Personal, Other, Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/058430, entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy; International Patent Application No. PCT/US2018/12209, entitled “PBRM1 Biomarkers Predictive of Anti-Immu; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Alexion Pharmaceuticals; alligent; Analysis Group; AstraZeneca; Bayer; Bristol Myers Squibb; Cerulean Pharma; Clinical Care Options; Corvus Pharmaceuticals; Eisai; EMD Serono; ESMO; Exelixis; Foundation Medicine; GlaxoSmithKline; Harborside Press; HERON; Financial Interests, Personal, Other, Medical writing and editorial assistance support: ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel. S.K. Pal: Financial Interests, Personal, Advisory Role: Astellas Pharma; Aveo; Bristol Myers Squibb; Eisai; Exelixis; Genentech; Ipsen; Myriad Pharmaceuticals; Novartis; Pfizer. All other authors have declared no conflicts of interest.

Background

¹⁷⁷Lu-PSMA-617 (Lu-PSMA-617) is a radiolabelled small-molecule with established efficacy and safety in mCRPC, that delivers β radiation to tumours expressing PSMA. Pembrolizumab, an anti-programmed death 1 inhibitor, has modest single agent anti-tumour activity in mCRPC. We hypothesise that β radiation can induce tumour cell death that is potentially immunogenic, and that addition of pembrolizumab to Lu-PSMA-617 can improve responses. PRINCE aimed to evaluate the safety and efficacy of the combination of Lu-PSMA-617 and pembrolizumab.

Methods

mCRPC patients (pts) with high PSMA expression without discordant FDG avid disease on paired PSMA and FDG PET/CT scans received up to 6 cycles of Lu-PSMA-617 (6-8 GBq) every 6 weeks in conjunction with 200mg of pembrolizumab every 3 weeks for up to 2 years. Co-primary endpoints were safety and 50% PSA response rate (PSA50-RR). Secondary endpoints included PSA-progression-free survival (PSA-PFS), radiographic PFS (rPFS) and overall survival (OS).

Results

37 pts (median age 72 years; prior docetaxel 73%; prior androgen receptor targeted agent 100%) received a median of 4 cycles of Lu-PSMA-617 and 8 doses of pembrolizumab. Median follow up was 38 weeks. PSA50-RR was 73% (27/37 [95% CI: 56-86]) and 7/9 (78%) pts with RECIST measurable disease had a partial response. rPFS and PSA-PFS at 24 weeks were 64% (95% CI: 45-79) and 68% (95% CI: 50-81) respectively. Common treatment related adverse events (TRAE) (≥10%) were mainly Grade (G) 1-2 and included xerostomia (76%), fatigue (43%), diarrhoea (11%), rash (22%), nausea (24%), elevated ALT (11%), pruritus (19%), and bone pain (11%). Haematologic TRAE included G2-3 anaemia (8%), G1-2 thrombocytopenia (14%), and G1 neutropenia (3%). G3 immune related AEs affecting one pt each included mucosal pemphigus, myasthenia gravis, optic neuritis, pancreatitis, pneumonitis, nephritis, amylase elevation, type 1 diabetes, and colitis in 2 pts. 4 (11%) pts discontinued treatment due to toxicity.

Conclusions

The combination of Lu-PSMA-617 and pembrolizumab had promising activity. Toxicities were consistent with those of single agent Lu-PSMA-617 and pembrolizumab.

Clinical trial identification

NCT03658447.

Legal entity responsible for the study

Peter MacCallum Cancer Centre.

Funding

This study was largely funded from a peer reviewed Victorian Cancer Agency Grant. We also received supplementary funding support from Merck Sharp and Dohme and Endocyte/Novartis.

Disclosure

S.K. Sandhu: Financial Interests, Institutional, Advisory Board, I have served on advisory boards for BMS. The contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: Bristol Myer Squibb; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for MSD. The e contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: Merck Sharp and Dohme; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for AstraZeneca. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: AstraZeneca; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for Novartis. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre: Novartis; Financial Interests, Institutional, Advisory Board, I have served on an advisory board for Merck Serono. The contracts for my service are set up with the institution and funds go into a research fund at the Peter MacCallum Cancer Centre: Merck Serono; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: Novartis; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: Genentech; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: Amgen; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: AstraZeneca; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: Merck Serono; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead: Merck Sharp and Dohme; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Janssen sponsored studies and don't receive any renumeration for this: Janssen; Non-Financial Interests, Principal Investigator, I am a principal investigator on several Novartis sponsored studies and dont receive any renumeration for this: Novartis; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Genentech sponsored studies and don't receive any renumeration for this: Genentech; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Bristol Myer Squibb sponsored studies and don't receive any renumeration for this: Bristol Myer Squibb; Non-Financial Interests, Other, I serve on the Independent Safety and Data Monitoring committee for 2 of Novartis sponsored studies and dont receive any compensation for this: Novartis; Non-Financial Interests, Principal Investigator, I am the Priincipal Investigator for several AstraZeneca sponsored studies and am not remunerated for this: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for several Janssen sponsored trials and i do not receive compensation for this: Janssen; Non-Financial Interests, Other, I serve on the steering committee for one AstraZeneca sponsored trial and I do not receive compensation for this: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for one Genentech sponsored trials and I do not receive compensation for this: Genentech; Non-Financial Interests, Other, I serve on the steering committee for a Bristol Myer Squibb sponsored trial and I do not receive renumeration for this: Bristol Myer Squibb. A.M. Joshua: Financial Interests, Institutional, Advisory Board, Serving on an advisory board. Funds were paid to the institution: Merck, Sharpe & Dhome. L. Emmett: Financial Interests, Personal, Speaker’s Bureau: Astellas; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Speaker’s Bureau: Mundipharma; Financial Interests, Personal, Speaker’s Bureau: Clarity Pharmaceuticals. L. Spain: Financial Interests, Personal, Advisory Board, < 5000 Euro. Chaired the Advisory Board on irAEs and how to improve networking: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker, < 5000 Euro. Invited speaker at COSA (Australian conference): Bristol Myers Squibb; Financial Interests, Institutional, Principal Investigator, PROpel Study, PI for eastern Health: AstraZeneca; Financial Interests, Institutional, Principal Investigator, MDV3800-06 Study, PI for Eastern Health: Pfizer; Financial Interests, Institutional, Principal Investigator, IPATential 150 Study, PI for Eastern Health: Roche. L.G. Horvath: Financial Interests, Personal, Advisory Board, Honorarium donated back to Chris O'Brien Lifehouse (My hospital): Imagion Biosystems; Non-Financial Interests, Personal, Member of the Board of Directors, No payment received: ANZUP (Australia and New Zealand Urogenital and Prostate) Clinical Trials Group; Financial Interests, Personal, Stocks/Shares, Stock Options: Imagion Biosystems; Financial Interests, Personal, Stocks/Shares: My Emergency Doctor; Financial Interests, Institutional, Principal Investigator, AMG160 Phase I Study and AMG509 Phase I Study: Amgen; Financial Interests, Institutional, Principal Investigator, ATG-017 Study: Antagene; Financial Interests, Institutional, Advisory Role, Steering Committee Member, ENZAMET Study and ENZARAD Study: ANZUP; Financial Interests, Institutional, Advisory Role, Steering Committee Member, DASL-HiCAP Study ANZUP; Financial Interests, Institutional, Principal Investigator, AB928CSP0003 Study: ARCUS; Financial Interests, Institutional, Principal Investigator, 9785-CL-0335 (ARCHES) Study: Astellas; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Principal Investigator, BGB-A317 Study, BGB-283 Study, BGB-A317-290 Study: Beigene; Financial Interests, Institutional, Principal Investigator, JPCM Study: Eli-Lilly; Financial Interests, Institutional, Principal Investigator, XL184-021 Study: Exelixis; Financial Interests, Institutional, Principal Investigator, FPT155-001 Study: Five Prime; Financial Interests, Institutional, Principal Investigator, GSK204697 Study: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator, Galahad Study, ACIS Study, Prevalence Study: Janssen-Cilag; Financial Interests, Institutional, Principal Investigator, SHR3680-002 Study: Jiangsu Hengrui Medicines; Financial Interests, Institutional, Principal Investigator, MK7684-001 Study, MK3475-991 Study: Merck Sharp & Dohme; Financial Interests, Institutional, Principal Investigator, C344102 Study: Pfizer. M. Crumbaker: Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role, Honorarium: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role, Honorarium: Pfizer. A. Anton: Financial Interests, Personal, Advisory Role, Honorarium: Amgen; Financial Interests, Personal, Advisory Role, Honorarium: Janssen; Financial Interests, Personal, Other, Travel: Amgen; Financial Interests, Personal, Invited Speaker, Travel: Astellas; Financial Interests, Institutional, Funding, Research funding: Amgen; Financial Interests, Institutional, Funding, Research funding: AstraZeneca; Financial Interests, Institutional, Funding, Research funding: Astellas; Financial Interests, Institutional, Funding, Research funding: Janssen; Financial Interests, Institutional, Funding, Research funding: Mundipharma. I.D. Davis: Financial Interests, Personal, Royalties, Authorship royalties for: Health Press; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Astellas; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: AstraZeneca; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Bayer; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Bristol Myers Squibb; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Eisai; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Exelixis; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Janssen; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Merck Sharpe & Dohme; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Movember Foundation; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Pfizer; Financial Interests, Institutional, Principal Investigator, Institutional support for clinical research: Roche/Genetech; Non-Financial Interests, Institutional, Member of the Board of Directors, Director and Chair: ANZUP Cancer Trials Group; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Astellas; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: AstraZeneca; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Bayer; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Bristol Myers Squibb; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Eisai; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Ipsen; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Janssen; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Merck/Pfizer; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Merck Sharpe & Dohme; Non-Financial Interests, Institutional, Advisory Role, All honoraria and payments are made directly to ANZUP. No pass-through payment: Roche. S. Williams: Financial Interests, Personal, Research Grant, Funding to perform laboratory work: Bristol Myers Squibb. R. Hicks: Financial Interests, Personal, Stocks/Shares: Telix Pharmaceuticals; Non-Financial Interests, Institutional, Advisory Role, Honorary Trustee. All honoraria is donated to the Peter MacCallum Cancer Centre: International Cancer Imaging Society; Non-Financial Interests, Institutional, Member of the Board of Directors, Honorary Director. All honoraria donated to the Peter MacCallum Cancer Centre: Neuroendocrine Cancer Foundation. M. Hofman: Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Mundipharma; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Institutional, Sponsor/Funding, research grant: Advanced Accelerator Applications, A Novartis Company; Financial Interests, Institutional, Sponsor/Funding, research grant: Endocyte. All other authors have declared no conflicts of interest.

Background

In ARCHES (NCT02677896), ENZA + ADT reduced risk of radiographic progression and improved secondary outcomes in men with mHSPC over PBO + ADT. Here we report the final OS (after 356 events), a key secondary endpoint in ARCHES and a critical benchmark of clinical efficacy, which was immature at the time of primary analysis.

Methods

Men with de novo or relapsed mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume and prior docetaxel use. At the time of data cut-off and unblinding, 180 (31.3%) patients treated with PBO + ADT crossed over to open-label ENZA + ADT. A stratified log-rank test was performed at a two-sided significance level of 0.04 for OS based on an O’Brien-Fleming boundary. Kaplan-Meier estimates of OS and time to subsequent antineoplastic therapy (TTNAnti) were reported and hazard ratios (HRs) were estimated from a stratified Cox proportional hazards model. Safety was assessed via treatment-emergent adverse events.

Results

Baseline characteristics were similar between treatment arms. As of the data cut-off of May 28, 2021, 397 (34.5%) patients remained on treatment, with a median follow-up of 44.6 months). Median treatment duration was 40.2 months on ENZA + ADT, 13.8 months on PBO + ADT, and 23.9 months for crossover patients. ENZA + ADT extended survival vs PBO + ADT (HR 0.66; 95% confidence interval 0.53, 0.81; p<0.0001) [Table] with similar results in most prespecified subgroups. ENZA + ADT continued to prolong TTNAnti vs PBO + ADT. The safety profile of ENZA + ADT vs PBO + ADT was consistent with findings from the primary analysis.

Conclusions

This final analysis demonstrates that ENZA + ADT significantly prolongs survival in men with mHSPC and, together with the acceptable safety profile, supports the clinical benefit of ENZA + ADT in men with mHSPC. Table: LBA25

Time to event efficacy endpoints

Clinical trial identification

NCT02677896.

Editorial acknowledgement

This study was funded by Astellas Pharma Inc. and Pfizer Inc., the co-developers of enzalutamide. Medical writing and editorial assistance were provided by Folabomi Oladosu, PhD, and Jane Beck, MA, from Complete HealthVizion, funded by the study sponsors.

Legal entity responsible for the study

Astellas Pharma Inc. and Pfizer Inc., the co-developers of enzalutamide.

Funding

Astellas Pharma Inc. and Pfizer Inc.

Disclosure

A.J. Armstrong: Financial Interests, Personal, Other, Consultant: Astellas; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Forma; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Dendreon; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: Janssen; Financial Interests, Institutional, Invited Speaker: Beigene; Financial Interests, Institutional, Invited Speaker: BMS; Financial Interests, Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Invited Speaker: Bayer; Financial Interests, Institutional, Invited Speaker: Astellas; Financial Interests, Institutional, Invited Speaker: Dendreon; Financial Interests, Institutional, Invited Speaker: Amgen. T. Iguchi: Financial Interests, Personal, Funding, Research Funding: Astellas, Bayer; Financial Interests, Personal, Advisory Role, Consulting or advisory: Astellas Pharma Inc., Bayer, Janssen; Financial Interests, Personal, Invited Speaker, Speakers Bureau: Astellas, Bayer, Janssen, Sanofi. A.A. Azad: Financial Interests, Personal, Other, Honoraria: Janssen, Astellas, Novartis, Tolmar, Amgen, Pfizer, Bayer, Telix Pharma, Bristol Myers Squibb, Merck Serono, AstraZeneca, Sanofi, Ipsen, Merck Sharp & Dohme, Noxopharm; Financial Interests, Personal, Advisory Role, Consulting or advisory: Astellas, Novartis, Janssen, Sanofi, AstraZeneca, Bristol Myers Squibb, Tolmar, Telix Pharma, Merck, Bayer, Ipsen, Merck Serono, Amgen, Noxopharm; Financial Interests, Personal, Funding, Research Funding: Astellas, Merck Serono, Novartis, Pfizer, Bristol Myers Squibb, Sanfi, AstraZeneca, GlaxoSmithKline, Aptevo Therapeutics, MedImmune, Bionomics, Synthorx, AstraZeneca, Ipsen; Financial Interests, Personal, Other, Travel, accomodations, expenses: Astellas, Sanofi, Merck Serono, Amgen, Janssen, Tolmar, Pfizer; Financial Interests, Personal, Invited Speaker, Speaker's Bureau: Astellas, Novartis, Amgen, Bayer, Janssen, Ipsen, Bristol-Myers, Merck Serono. R.Z. Szmulewitz: Financial Interests, Personal, Funding, Research Funding: AbbVie, Astellas Pharma, Incyte, Macrogenics, Janssen Oncology; Financial Interests, Personal, Other, Honoraria: stellas Pharma; Financial Interests, Personal, Advisory Role, Consulting or advisory: AstraZeneca, AbbVie, Exelixis, Merck, Amgen, Janssen Oncology, Sanofi, Astellas Pharma, PFizer; Financial Interests, Personal, Other, Travel, accomodations, expenses: Corcept Therapeutics. J. Holzbeierlein: Financial Interests, Institutional, Funding, Research Funding: MDxHealth; Financial Interests, Personal, Advisory Role, Consulting or advisory: Basilea; Non-Financial Interests, Personal, Other, Authorship: Astellas. A. Villers: Financial Interests, Personal, Advisory Role, Consulting or advisory: Astellas Pharam Inc; Financial Interests, Personal, Research Grant, Research Funding: Astellas Pharma Inc, Janssen Oncology. A. Alcaraz: Financial Interests, Personal, Advisory Role, Consulting or advisory: Astellas Pharma Inc; Financial Interests, Personal, Other, Travel, accomodations, expenses: Olympus, Ipsen, Janssen, Bayer. B.Y. Alekseev: Financial Interests, Personal, Funding, Research Funding: AstraZeneca, Merck, Sanofi, Bayer, Astellas Pharma, Janssen, Bristol Myers Squibb, Bavarian Nordic, Pfizer, ICON Clinical Research, Eisai, MSD, Roche; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Astellas Pharma, Ferring, Eisai, Janssen, Bayer, MSD, Merck, Pfizer, Roche, Sanofi, Bristol Myers Squibb; Financial Interests, Personal, Advisory Role, Consulting or advisory: AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Ferring, Janssen, Merck, Sanofi, Pfizer, MSD, Roche, Eisai; Financial Interests, Personal, Other, Travel, accomodations, expenses: AstraZeneca, Astellas Pharma, Bayer, Bristol Myers Squibb, Janssen, MSD, Pfizer, Sanofi; Financial Interests, Personal, Invited Speaker, Speaker's Bureau: Janssen, Sanofi, Ferring, Astellas Pharma, Pfizer, AstraZeneca, Bayer, Merck, Bristol Myers Squibb, MSD, Eisai, Roche. N.D. Shore: Financial Interests, Personal, Advisory Role, Consulting or advisory: Bayer, Janssen Scientific Affairs, Dendreon, Tolmar, Ferring, Astellas/Medivation, Amgen, Pfizer, AstraZeneca, Genentech/Roche, Myovant Sciences, Astellas Pharma, AstraZeneca, Merck; Financial Interests, Personal, Invited Speaker, Speakers Bureau: anssen, Bayer, Dendreon. D.P. Petrylak: Financial Interests, Personal, Funding, Research Funding: Progenics, Sanofi, Endocyte, Genentech, Merck, Astellas, Novartis, AstraZeneca, Bayer, Lilly, Innocrin Pharma, MedImmune, Pfizer, Roche, Seattel Genetics, Clovis Oncology, Bristol Myers Squibb, Advanced Accelerator Applications, Agensys, BiXCell therapeu; Financial Interests, Personal, Ownership Interest, Stock or Ownership: Bellicum Pharmaceuticals, Tyme; Financial Interests, Personal, Expert Testimony: Celgene, Sanofi; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Astellas Pharma, Ferring, Eisai, Janssen, Bayer, MSD, Merck, Pfizer, Roche, Sanofi, Bristol Myers Squibb; Financial Interests, Personal, Advisory Role, Consulting or advisory: Bayer, Exelixis, Pfizer, Roche, Astellas Pharma, AstraZeneca, Lilly, Amgen, Boehringer, Bristol Myers Squibb, Clovis Oncology, Incyte, Janssen, Pharmacyclics, Seattle Genetics, Urogen Pharma, Advanced Accelerator Applications, Ipsen, Bicycle Therapeutcs,. B. Rosbrook: Financial Interests, Personal, Full or part-time Employment, Pfizer employee: Pfizer. F. Zohren: Financial Interests, Personal, Full or part-time Employment, Pfizer employee: Pfizer; Financial Interests, Personal, Ownership Interest, Stock or Ownership: Pfizer, Allovir. S. Yamada: Financial Interests, Personal, Full or part-time Employment, Astellas Pharma employee: Astellas Pharma Inc. G.P. Haas: Financial Interests, Personal, Full or part-time Employment, Astellas Pharma employee: Astellas Pharma Inc. A. Stenzl: Financial Interests, Personal, Advisory Role, Consulting or advisory: psen, Roche, Janssen, Alere, Bristol Myers Squibb, Steba Biotech, Synergo, Ferring; Financial Interests, Personal, Funding, Research Funding: Karl Storz, Astellas Pharma, AstraZeneca , Medivation, Janssen, Johnson & Johnson, Roche, Cepheid, Immatics, Bayer, Novartis, Amgen, GenomeD; Financial Interests, Personal, Expert Testimony: GBA Pharma; Financial Interests, Personal, Other, Travel, accomodations, expenses: Janssen, Ipsen, Sanofi/Aventis, CureVac, Ferring, Astellas Pharma, Amgen, AstraZeneca.