454O - A phase (Ph) I/II trial of the CXCR2 antagonist AZD5069 in combination with enzalutamide (ENZA) in patients (pts) with metastatic castration resistant prostate cancer (mCRPC)

Background

Tumour-infiltrating myeloid cells drive mCRPC growth and therapeutic resistance, in part through IL-23 and NRG1 secretion. Inhibition of myeloid infiltration by disrupting the CXCR2 receptor axis can reverse ENZA resistance in PC models. AZD5069 is a selective CXCR2 antagonist.

Methods

This Ph 1/2 multi-centre study evaluated the combination of AZD5069 and ENZA in pts with mCRPC, ECOG PS2, who had progressed on 1 novel anti-androgen therapy (NAAT). A Ph1 ‘3+3’ dose-escalation design evaluated AZD5069 at 40, 80, 120, 160, and 320 mg BD in combination with ENZA at 160 mg OD. The Ph2 expansion utilised Simon’s 2-stage design for 2 potential expansion arms. The primary objective in Ph1 was to establish the RP2Ds. The primary endpoint in Ph2 was composite response rate (PSA fall >50%, RECIST, or CTC conversion). Secondary endpoints included: PK, PD, radiologic PFS and OS.

Results

As of 10FEB2022, 21 DLT-evaluable pts were enrolled to the Ph1; 11 pts were enrolled in Ph2. Pts had 6 median prior lines of therapy. Since antitumour activity was observed at AZD5069 160 mg BD plus ENZA, this dose level was expanded. PK studies showed ENZA-induced CYP3A4 metabolism of AZD5069; AZD5069 was therefore escalated to 320mg BD. No DLT was observed in Ph1 or 2. The main G3-4 treatment emergent adverse events (>10%) was afebrile, uncomplicated neutropenia (Ph1: 11/21, Ph2: 4/11), an on-target effect of AZD5069. 3/21 response-evaluable pts had partial responses (PR) and 2/21 had stable disease (SD) lasting >6 months (mo) in Ph1. At AZD5069 80 mg BD, 1/3 pt had SD (16 mo); at 120 mg BD, 1/3 pt had PR (-31% by RECIST, PSA -89%, PFS: 11 mo); at 160 mg BD, 1/6 pt had PR (PSA -82%, -20% by RECIST, PFS: 8 mo) and 1/6 pt had SD (8 mo); and at 320 mg BD, 1/6 pt had PR (PSA -64%, PFS: 5 mo, ongoing). In the Ph2 expansion at the lower RP2D of AZD5069 160 mg BD plus ENZA, 1/11 pt had 33% PSA fall and another had SD (11 mo). All patients with PR/SD>6 mo previously progressed on ENZA.

Conclusions

The combination of AZD5069 and ENZA is tolerable and has antitumor activity in mCRPC. We provide clinical evidence for direct targeting of myeloid chemotaxis as a therapeutic strategy in mCRPC.

Clinical trial identification

NCT03177187.

Editorial acknowledgement

Legal entity responsible for the study

Institute of Cancer Research.

Funding

AstraZeneca, Prostate Cancer Foundation, Prostate Cancer UK, National Institute of Health and Research Biomedical Research Centre. This academic sponsored study received enzalutamide from Astellas and AZD5069 from AstraZeneca.

Disclosure

A. Sharp: Non-Financial Interests, Principal Investigator, Clinical trial in progress: Astrazenica, Amgen, Nurix; Non-Financial Interests, Principal Investigator, Clinical trial in set up: Exelixis; Non-Financial Interests, Institutional, Product Samples, Access to IMP as a gift for research: AstraZenica; Other, Paid consultancy: D.E Research. U. Vogl: Financial Interests, Institutional, Advisory Board: Roche, Pfizer, Merck, Janssen; Financial Interests, Institutional, Invited Speaker: Astellas, Health Books; Financial Interests, Institutional, Expert Testimony: Janssen; Financial Interests, Personal, Advisory Board: Eli Lilly, Servier, Pfizer, Janssen, MSD, Bayer, BMS; Financial Interests, Personal, Invited Speaker: Samo. I. Colombo: Financial Interests, Institutional, Funding, Honoraria: AstraZeneca, GLAXOSMITHKLINE, Novartis; Financial Interests, Personal, Advisory Role: MSD Oncology; Financial Interests, Institutional, Funding: MSD, Bayer, Osmania Pharmaceutical AB; Financial Interests, Personal, Other: Tesario. A. Stathis: Financial Interests, Institutional, Expert Testimony: Bayer; Financial Interests, Institutional, Advisory Board: Janssen, roche, Eli Lilly; Financial Interests, Institutional, Invited Speaker: Pfizer, Merck, Roche, Novartis, ADC Therapeutics, AbbVie, Bayer, Philogen, Cellestia, AstraZeneca. S. Jain: Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen; Financial Interests, Personal and Institutional, Invited Speaker, Research consumables: Boston Scientific. F. Raynaud: Financial Interests, Institutional, Research Grant: Cancer Research UK; Financial Interests, Institutional, Royalties, Investigator Award For Abiraterone: Institute of Cancer Research. A. Alimonti: Financial Interests, Personal, Stocks/Shares: Oncosence; Financial Interests, Personal, Ownership Interest: Bottega Organica; Financial Interests, Personal, Royalties, US11235017B2No income yet: Altergon SA; Financial Interests, Institutional, Royalties, US11168134B2No income: Fondazione Per L'istituto Oncologico Di Ricerca (IOR); Financial Interests, Personal, Royalties, US9668961B2No income yet: ATRAHASIS Srl; Financial Interests, Institutional, Research Grant: Dompé Farmaceutici, IBSA Institut Biochimique. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Pfizer, Merck Serono, AstraZeneca, Harpoon, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GlaxoSmithKline. All other authors have declared no conflicts of interest.