MedPath

Etrumadenant Advanced Drug Monograph

Published:Sep 12, 2025

Generic Name

Etrumadenant

Drug Type

Small Molecule

Chemical Formula

C23H22N8O

CAS Number

2239273-34-6

Etrumadenant (AB928): A Comprehensive Monograph on a First-in-Class Dual Adenosine A2a/A2b Receptor Antagonist for Cancer Immunotherapy

I. Executive Summary

Etrumadenant (AB928) is an investigational, orally bioavailable, small molecule therapeutic agent representing a first-in-class dual antagonist of the adenosine A2a (A2aR) and A2b (A2bR) receptors. Developed by Arcus Biosciences, etrumadenant was designed to counteract a fundamental mechanism of tumor immune evasion by targeting the highly immunosuppressive adenosine signaling pathway within the tumor microenvironment (TME). The scientific rationale is robust: by blocking the effects of high concentrations of adenosine—a byproduct of tumor cell metabolism and death—etrumadenant aims to reinvigorate the anti-tumor activity of various immune cells, including T-lymphocytes and myeloid cells, thereby unleashing a more effective immune response against cancer.

The clinical development of etrumadenant has yielded a complex and dichotomous profile. The agent achieved a remarkable and unprecedented clinical success in the Phase 1b/2 ARC-9 trial, where its combination with chemotherapy and immunotherapy resulted in a statistically significant and clinically profound improvement in overall survival for patients with third-line metastatic colorectal cancer (mCRC). This result provided clear clinical validation for its mechanism of action. Conversely, the development program has faced significant setbacks. Trials in other indications, most notably metastatic castration-resistant prostate cancer (mCRPC) and EGFR-mutated non-small cell lung cancer (NSCLC), failed to demonstrate sufficient clinical benefit, leading to the discontinuation of development in those settings.

This juxtaposition of striking success and clear failure underscores the critical importance of the specific tumor context in determining the efficacy of adenosine pathway inhibitors. The trajectory of etrumadenant was further complicated by strategic and regulatory dynamics. Following the positive ARC-9 results, discussions with the U.S. Food and Drug Administration (FDA) highlighted the need for a large, confirmatory Phase 3 trial. This requirement, coupled with a strategic re-evaluation by development partner Gilead Sciences, led to Gilead returning the rights to the asset and Arcus Biosciences subsequently announcing a "pause" in its development. Consequently, etrumadenant stands as a compelling case study of a scientifically promising therapeutic agent whose future is shaped not only by its clinical efficacy but also by the formidable regulatory and commercial hurdles inherent in late-stage oncology drug development.

II. Scientific Rationale and Pharmacological Profile

2.1. The Adenosine Axis: A Key Immunosuppressive Pathway in the Tumor Microenvironment (TME)

The TME is a complex ecosystem characterized by conditions such as hypoxia, inflammation, and high cell turnover, which collectively create a profoundly immunosuppressive milieu that facilitates tumor growth and metastasis. Central to this immunosuppression is the ATP-adenosine signaling pathway, often referred to as the adenosine axis. In response to cellular stress, damage, or death—processes exacerbated by cytotoxic chemotherapy—cancer cells release large quantities of adenosine triphosphate (ATP) into the extracellular space.[1]

This extracellular ATP is not directly immunosuppressive; rather, it serves as a substrate for a two-step enzymatic cascade mediated by cell-surface ectonucleotidases. First, CD39 (ectonucleoside triphosphate diphosphohydrolase-1) hydrolyzes ATP and ADP into adenosine monophosphate (AMP). Subsequently, CD73 (ecto-5'-nucleotidase) dephosphorylates AMP to generate the final product, adenosine.[2] This extracellular adenosine functions as a potent signaling molecule that suppresses the body's innate and adaptive immune responses to the tumor.

Adenosine exerts its effects by binding to one of four G protein-coupled receptors: A1, A2a, A2b, and A3. The A2a and A2b receptors are of primary importance in cancer immunology. These receptors are expressed on a wide array of immune cells critical for anti-tumor immunity, including T-lymphocytes, natural killer (NK) cells, dendritic cells (DCs), macrophages, and myeloid-derived suppressor cells (MDSCs).[5] The activation of A2aR on T cells and NK cells impairs their activation, proliferation, and cytotoxic functions, effectively blunting their ability to kill cancer cells.[1] Simultaneously, activation of A2aR and A2bR on myeloid cells like DCs and macrophages skews them toward an anti-inflammatory, pro-tumorigenic phenotype, further dampening the immune response.[4] Beyond its immunomodulatory roles, A2bR signaling on cancer cells themselves has been implicated in promoting tumor cell proliferation, angiogenesis, and metastasis, representing a direct pro-growth pathway.[7] By hijacking this natural, homeostatic pathway, tumors create an "adenosinergic halo" that serves as a powerful shield against immune destruction. Therefore, pharmacologic blockade of the A2a and A2b receptors presents a compelling therapeutic strategy to reverse this immunosuppression and restore effective anti-tumor immunity.

2.2. Chemical Identification and Physicochemical Properties

Etrumadenant is a synthetic, achiral small molecule belonging to the chemical classes of amines, nitriles, pyridines, pyrimidines, and triazoles.[8] Its identity is well-defined across multiple chemical and drug databases. A comprehensive summary of its identifiers and physicochemical properties is provided in Table 1.

The molecular structure of etrumadenant was rationally designed to confer properties suitable for an orally administered therapeutic. This is a critical feature for a drug intended for chronic or long-term use in combination with other therapies, as oral administration significantly enhances patient convenience, reduces healthcare system burden, and can improve treatment adherence compared to intravenous formulations. The molecule's physicochemical characteristics are consistent with this objective. It adheres to Lipinski's "Rule of Five," a set of guidelines used to predict a drug's potential for oral bioavailability, with zero reported violations.[11] Key parameters supporting this include a molecular weight under 500 Da, a logP value in an acceptable range for membrane permeability, and appropriate numbers of hydrogen bond donors and acceptors.[11] The predicted bioavailability is 1, further underscoring the success of its design for oral administration.[11]

PropertyValueSource(s)
Generic NameEtrumadenant11
SynonymsAB928, AB-928, A2aR/A2bR antagonist-111
DrugBank IDDB1750611
CAS Number2239273-34-613
ChEMBL IDCHEMBL474038312
Molecular FormulaC23​H22​N8​O11
Molecular Weight426.48 g/mol (Average)11
Monoisotopic Weight426.1917 g/mol11
IUPAC Name3-[2-Amino-6-[[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl]triazol-4-yl]pyrimidin-4-yl]-2-methylbenzonitrile13
SMILESN#CC1=CC=CC(C2=NC(N)=NC(C3=CN(CC4=NC(C(C)(O)C)=CC=C4)N=N3)=C2)=C1C8
InChIKeyBUXIAWLTBSXYSW-UHFFFAOYSA-N13
Water Solubility0.0492 mg/mL11
logP2.56 - 3.6711
pKa (Strongest Acidic)13.9411
pKa (Strongest Basic)3.9811
Rule of Five ComplianceYes (0 violations)11
Polar Surface Area139.42 A˚211
Rotatable Bond Count511
Table 1: Chemical and Physicochemical Properties of Etrumadenant. This table consolidates key identification and property data from various chemical and pharmacological databases.

2.3. Molecular Mechanism of Action

Etrumadenant functions as a potent, selective, and competitive antagonist of the human adenosine A2a and A2b receptors.[6] Its high affinity for these targets is demonstrated by low nanomolar dissociation constants (

Kd​), reported as 1.4 nM for A2aR and 2.0 nM for A2bR.[14] The drug also exhibits selectivity, with a reported inhibitory constant (

Ki​) of 64 nM for the A1 receptor, indicating significantly weaker activity at this subtype, and only weak inhibition of the A3 receptor at micromolar concentrations.[8]

The decision to develop a dual antagonist rather than a more selective A2aR inhibitor was a deliberate and central element of the drug's design philosophy. This strategy is based on the distinct yet complementary roles of the A2a and A2b receptors in orchestrating the immunosuppressive TME. A2aR is the primary receptor responsible for suppressing the cytotoxic functions of T cells and NK cells.[7] However, A2bR is also highly expressed on myeloid cells and some cancer cells, where its activation contributes to immunosuppression and promotes tumor growth and metastasis.[7] A therapeutic agent targeting only A2aR might leave the A2bR signaling pathway intact, providing an escape mechanism for adenosine-mediated tumor promotion. Arcus Biosciences specifically designed etrumadenant to block both receptors, ensuring a more comprehensive and robust blockade of the entire adenosine signaling axis across all relevant immune cell populations within the TME.[7]

Upon oral administration, etrumadenant competes with the high concentrations of adenosine present in the TME for binding to A2aR and A2bR on the surface of tumor-infiltrating immune cells.[5] By occupying the receptor binding sites without initiating downstream signaling, etrumadenant prevents adenosine from exerting its immunosuppressive effects. This blockade is intended to restore and enhance the natural anti-tumor functions of the immune system. Specifically, A2aR/A2bR inhibition is expected to activate and increase the proliferation of various immune cells, abrogate adenosine-mediated immunosuppression, and ultimately unleash potent anti-tumor immune responses that lead to the killing of cancer cells.[5] Preclinical and clinical biomarker data support this mechanism, showing that etrumadenant treatment can reverse adenosine-regulated gene expression signatures and increase T-cell activation within tumors.[3]

2.4. Pharmacokinetics and Metabolism (ADME)

The pharmacokinetic profile of etrumadenant has been characterized in healthy volunteers and through population pharmacokinetic (PopPK) and physiologically-based pharmacokinetic (PBPK) modeling using data from numerous clinical trials. These studies have defined its absorption, distribution, metabolism, and excretion (ADME) properties and revealed a clinically favorable dosing profile.

Absorption: Following a single oral dose in healthy volunteers (ARC-19 study), etrumadenant is absorbed relatively quickly. Plasma concentrations begin to increase within 30 minutes of administration, reaching maximum concentration (Cmax​) between 0.5 and 2 hours post-dose.[17]

Distribution: Specific tissue distribution data is not extensively detailed; however, the drug is systemically available and can be detected in the blood for up to 10 days after a single dose, suggesting a reasonable volume of distribution and half-life.[17]

Metabolism: While the precise metabolic pathways have not been fully elucidated in the provided materials, studies in healthy volunteers using radiolabeled drug indicate that the parent compound is the primary circulating moiety.[17]

Excretion: Elimination of etrumadenant occurs via both renal (urine) and fecal routes. The process is relatively efficient, with over half of the administered dose being cleared from the body within the first two days. Near-complete excretion, accounting for 96.4% of the dose, is achieved after 12 days.[17]

A particularly significant finding from the comprehensive PopPK and PBPK modeling, which integrated data from 11 separate studies, relates to the drug's robust absorption profile under various clinical conditions. The analysis concluded that co-administration of etrumadenant with food or with acid-reducing agents (ARAs)—including proton pump inhibitors (PPIs), histamine H2-receptor antagonists (H2RAs), and antacids—has no clinically significant effect on its pharmacokinetics.[18] While administration with food was associated with a minor decrease in

Cmax​ (10.6%) and a slight increase in total exposure (AUC, 8%), and PPI use was associated with a 16.7% decrease in Cmax​ and a 10.2% decrease in AUC, these variations were not deemed clinically meaningful.[19] This represents a substantial practical advantage in the clinical setting. Cancer patients often suffer from gastrointestinal side effects from chemotherapy and frequently require ARAs. Furthermore, their nutritional intake can be variable. A drug whose absorption and bioavailability are independent of these factors is far simpler and safer to administer, eliminating the need for complex dosing instructions, minimizing the risk of drug-drug interactions at the absorption level, and ultimately improving the likelihood of consistent therapeutic exposure and patient adherence.[18]

III. Preclinical Evidence and Proof-of-Concept

3.1. In Vitro Immunomodulatory Activity

The biological activity of etrumadenant was first established through a series of in vitro experiments using human immune cells, which provided strong proof-of-concept for its intended mechanism of action. These studies consistently demonstrated the ability of etrumadenant to reverse the immunosuppressive effects of adenosine. In co-culture systems, etrumadenant was shown to effectively inhibit the ability of adenosine to suppress the activation of both human CD4+ and CD8+ T cells, which are the primary effector cells responsible for killing tumors.[14]

The drug's effect on antigen-presenting cells was also investigated. Monocyte-derived dendritic cells (moDCs), which are crucial for initiating T-cell responses, were differentiated in the presence of adenosine, diminishing their capacity to stimulate T-cell activity. The addition of etrumadenant significantly reversed this suppression, restoring the ability of the moDCs to induce interferon-gamma (IFN-γ) secretion from allogeneic CD4+ T-cells in a mixed leukocyte reaction (MLR).[20] This finding is critical, as it shows that etrumadenant can act at an early stage of the immune response to enhance T-cell priming.

To further probe the molecular underpinnings of this effect, multiplexed gene expression profiling using NanoString technology was employed. This analysis identified a specific set of 39 genes whose expression is regulated by adenosine during the differentiation of moDCs. Etrumadenant was shown to rescue these adenosine-driven changes in gene expression, providing direct molecular evidence that the drug engages its target and reverses its downstream biological consequences at the transcriptional level.[5]

3.2. In Vivo Antitumor Efficacy

Following the promising in vitro results, the anti-tumor efficacy of etrumadenant was evaluated in multiple syngeneic mouse tumor models, which allow for the study of a therapeutic agent in the context of a fully functional immune system. These in vivo studies confirmed that etrumadenant could translate its immunomodulatory activity into tangible anti-tumor effects. Administration of etrumadenant stimulated the anti-tumor immune response, resulting in suppressed tumor growth and an associated increase in the infiltration of immune cells into the tumor microenvironment.[5]

The potential for etrumadenant to work in combination with other anti-cancer therapies was a key focus of the preclinical program. In an AT3-OVA tumor model, etrumadenant administered as a single agent produced a small but significant decrease in tumor growth rate. However, when combined with the chemotherapeutic agent doxorubicin, it resulted in significantly reduced tumor growth rates compared to chemotherapy alone.[14] This provided a strong rationale for combining etrumadenant with chemotherapy in clinical trials, based on the hypothesis that chemotherapy-induced cell death would increase extracellular ATP and subsequent adenosine production, making tumors more susceptible to adenosine receptor blockade.

Furthermore, in a B16/F10 melanoma syngeneic mouse model, etrumadenant demonstrated synergistic activity with an anti-PD-1 antibody, leading to a greater reduction in tumor growth than either agent alone.[20] This finding was particularly important as it provided the foundational evidence for combining etrumadenant with immune checkpoint inhibitors, a strategy that would become central to its clinical development program.

IV. Clinical Development Program: Efficacy and Outcomes

The clinical development of etrumadenant has been extensive, spanning multiple tumor types and therapeutic combinations. The program has been characterized by a notable divergence in outcomes, with remarkable success in certain indications and clear failures in others. An overview of the major clinical trials is presented in Table 2.

Trial IdentifierNCT NumberPhaseIndication(s)Key Combination AgentsStatus
ARC-9NCT046608121b/2Metastatic Colorectal Cancer (mCRC)Zimberelimab, FOLFOX, BevacizumabRecruitment Complete
ARC-7NCT042628562Non-Small Cell Lung Cancer (NSCLC)Domvanalimab, ZimberelimabActive, Not Recruiting
ARC-6NCT043818321b/2Metastatic Castrate-Resistant Prostate Cancer (mCRPC)Zimberelimab, Docetaxel, Enzalutamide, etc.Completed
ARC-4NCT038463101/1bEGFRm+ NSCLCZimberelimab, ChemotherapyTerminated
ARC-3NCT037206781/1bmCRCmFOLFOX-6Completed
NCT05024097NCT050240971/2Rectal CancerZimberelimab, ChemoradiationRecruiting
NCT05886634NCT058866342Sarcomas (incl. Dedifferentiated Liposarcoma)ZimberelimabActive, Not Recruiting
Morpheus-CRCNCT035551491/2mCRCAtezolizumab, Bevacizumab, etc.Terminated
Table 2: Summary of Major Clinical Trials for Etrumadenant. This table provides a high-level overview of the key studies in the etrumadenant clinical development program.

4.1. Metastatic Colorectal Cancer (mCRC): A Story of Unprecedented Efficacy

4.1.1. The ARC-9 Trial (NCT04660812): Landmark Results in Third-Line mCRC

The ARC-9 study stands as the pinnacle of etrumadenant's clinical development, providing compelling evidence of its efficacy in a difficult-to-treat patient population. This Phase 1b/2, open-label, randomized trial was designed to evaluate etrumadenant-based combinations in patients with mCRC.[1] Cohort B of the study enrolled 112 patients with refractory mCRC who had progressed on standard oxaliplatin- and irinotecan-containing chemotherapy regimens.[23] Patients were randomized 2:1 to receive either the experimental four-drug regimen of

etrumadenant, zimberelimab (an anti-PD-1 antibody), FOLFOX chemotherapy, and bevacizumab (EZFB), or the standard-of-care control, regorafenib.[23]

The results, reported with a median follow-up of 20.4 months, were unequivocally positive and demonstrated a dramatic improvement in outcomes for the EZFB arm. The trial successfully met its primary and key secondary endpoints of progression-free survival (PFS) and overall survival (OS), respectively.

  • Overall Survival (OS): Patients in the EZFB arm achieved a median OS of 19.7 months, more than double the 9.5 months observed in the regorafenib arm. This represented a 63% reduction in the risk of death (Hazard Ratio 0.37; 95% CI 0.22-0.63; p=0.0003).[23] The 19.7-month median OS is the longest ever reported in a randomized trial for this third-line mCRC patient population.[25]
  • Progression-Free Survival (PFS): The EZFB regimen nearly tripled the median PFS to 6.2 months, compared to 2.1 months for regorafenib. This corresponded to a 73% reduction in the risk of disease progression or death (HR 0.27; 95% CI 0.17-0.43; p<0.0001).[23]
  • Objective Response Rate (ORR): The confirmed ORR was 17.3% for the EZFB arm, a more than six-fold improvement over the 2.7% ORR in the regorafenib arm.[23]

A summary of these key outcomes is provided in Table 3.

Efficacy EndpointEZFB Regimen (n=75)Regorafenib (n=37)Hazard Ratio (95% CI) / p-value
Median Overall Survival (OS)19.7 months9.5 monthsHR 0.37 (0.22-0.63); p=0.0003
Median Progression-Free Survival (PFS)6.2 months2.1 monthsHR 0.27 (0.17-0.43); p<0.0001
Confirmed Objective Response Rate (ORR)17.3%2.7%N/A
Median Duration of Response (DOR)11.5 monthsNot EvaluableN/A
Table 3: Key Efficacy Outcomes of the ARC-9 Trial (Cohort B). Data as of November 13, 2023 data cut-off.23

Crucially, the clinical efficacy was supported by translational biomarker data that provided direct evidence of etrumadenant's on-target mechanism of action in patients. Transcriptomic profiling of paired tumor biopsies taken at baseline and on-treatment revealed that the EZFB regimen led to a significant reduction in the expression of the NR4A gene family (NR4A1, NR4A2, NR4A3), which are known to be regulated by adenosine signaling. This reduction was accompanied by a significant increase in a T-cell activation gene expression signature, consistent with the hypothesis that etrumadenant reverses adenosine-mediated immunosuppression within the tumor.[3] Furthermore, analysis of baseline tumor tissues showed that patients whose tumors expressed CD73—the enzyme responsible for generating adenosine—derived a significantly greater PFS and OS benefit from the EZFB regimen compared to the control, directly linking the drug's mechanism to its clinical benefit.[3]

4.1.2. The ARC-3 Trial (NCT03720678): Foundational Evidence

The success of ARC-9 was built upon the encouraging results of the earlier Phase 1/1b ARC-3 study. This trial provided the initial clinical proof-of-concept for etrumadenant in mCRC, evaluating its combination with mFOLFOX-6 chemotherapy. The study established that the combination was well-tolerated, with etrumadenant not adding significant toxicity to that expected from the chemotherapy backbone.[26] In a heavily pretreated third-line-plus cohort, the combination demonstrated a median PFS of 4.2 months and a median OS of 13.6 months, both of which compared favorably to historical data for standard-of-care therapies.[26] These promising early signals of safety and efficacy provided the necessary justification to advance the program into the larger, randomized ARC-9 study.[1]

4.2. Non-Small Cell Lung Cancer (NSCLC): Nuanced and Indication-Specific Outcomes

4.2.1. The ARC-7 Trial (NCT04262856): Assessing the Triplet Combination

The ARC-7 trial was a randomized, open-label Phase 2 study designed to explore the contribution of inhibiting both the TIGIT and adenosine pathways in addition to PD-1 blockade. The trial enrolled treatment-naïve patients with metastatic NSCLC characterized by high PD-L1 expression (Tumor Proportion Score ≥50%) and no EGFR or ALK mutations.[29] Patients were randomized 1:1:1 to one of three arms: zimberelimab (anti-PD-1) monotherapy, domvanalimab (anti-TIGIT) plus zimberelimab (the doublet), or etrumadenant plus domvanalimab and zimberelimab (the triplet).[29]

The results demonstrated that both combination arms containing the anti-TIGIT antibody domvanalimab were superior to zimberelimab monotherapy. However, the addition of etrumadenant to the doublet did not lead to a further substantial improvement in efficacy outcomes.

Efficacy EndpointZimberelimab (Z) (n=44)Domvanalimab + Zimberelimab (DZ) (n=44)Etrumadenant + Domvanalimab + Zimberelimab (EDZ) (n=45)
Median PFS (months)5.412.010.9
PFS Hazard Ratio vs Z-0.550.65
Confirmed ORR (%)27%41%40%
Table 4: Key Efficacy Outcomes of the ARC-7 Trial. Data as of August 31, 2022 data cut-off.30

As shown in Table 4, with a median follow-up of 11.8 months, the median PFS was 12.0 months for the doublet and 10.9 months for the triplet, both markedly better than the 5.4 months for monotherapy. The ORRs were also similar for the doublet (41%) and triplet (40%), and both were superior to monotherapy (27%).[30] While the triplet arm performed well, these data suggested that in this specific patient population, the primary driver of the enhanced efficacy over PD-1 monotherapy was the addition of the anti-TIGIT antibody, with etrumadenant providing little to no additional benefit.

4.2.2. The ARC-4 Trial (NCT03846310): A Setback in EGFR-Mutated NSCLC

In contrast to the activity seen in PD-L1-high NSCLC, the development of etrumadenant for a different subset of lung cancer patients was unsuccessful. The ARC-4 trial was a randomized Phase 1/1b study evaluating etrumadenant plus zimberelimab and chemotherapy in patients with metastatic, EGFR-mutation positive (EGFRm+) NSCLC who had progressed on prior tyrosine kinase inhibitor (TKI) therapy.[32] The study failed to show differentiated clinical activity for the etrumadenant-containing arm compared to the control arm of zimberelimab and chemotherapy.[33] This lack of benefit led Arcus to de-prioritize and halt the development of etrumadenant for this specific indication.[33]

4.3. Metastatic Castration-Resistant Prostate Cancer (mCRPC): Discontinuation of Development

4.3.1. The ARC-6 Trial (NCT04381832): Failure to Show Sufficient Benefit

The development program for etrumadenant in mCRPC followed a trajectory from initial promise to ultimate disappointment. The ARC-6 trial was a multi-cohort, Phase 1b/2 platform study designed to evaluate various etrumadenant-based combinations.[34] Early, single-arm data from a cohort evaluating etrumadenant plus zimberelimab and docetaxel chemotherapy were encouraging, with a reported composite ORR of 41% and a PSA response rate of 35%.[36]

However, these promising early signals did not translate into success in the randomized stage of the trial. In the portion of the study that compared the triplet combination to docetaxel alone, the etrumadenant-containing regimen failed to demonstrate a sufficient clinical benefit over the control arm.[37] Based on this underwhelming efficacy data, Arcus Biosciences and Gilead announced in August 2023 that they were deprioritizing and discontinuing the development of etrumadenant for mCRPC.[37]

4.4. Investigations in Other Solid Tumors

Beyond the major programs in CRC, NSCLC, and prostate cancer, etrumadenant has been or is being investigated in several other solid tumors. These studies aim to explore the potential of adenosine receptor blockade in a broader range of cancer types.

  • Rectal Cancer: A Phase 1/2 trial (NCT05024097) is actively recruiting patients to evaluate etrumadenant in combination with zimberelimab and standard chemoradiotherapy.[39]
  • Sarcomas: A Phase 2 trial (NCT05886634) is investigating etrumadenant plus zimberelimab in patients with sarcomas, including dedifferentiated liposarcoma and other soft tissue sarcomas. The trial is active but no longer recruiting new patients.[41]
  • Other Malignancies: Earlier Phase 1 trials have been completed in a wide range of solid tumors, including bladder, breast, endometrial, gastroesophageal, head and neck, melanoma, ovarian, and renal cell cancers, primarily to establish safety and dosing.[11] Additionally, a multi-arm Phase 1/2 platform study in mCRC (Morpheus-CRC, NCT03555149), which included an etrumadenant combination arm, was terminated.[42]

V. Integrated Safety and Tolerability Analysis

5.1. Overall Safety Profile

Across its extensive clinical development program, etrumadenant has generally demonstrated a favorable and manageable safety profile. A key observation from multiple combination studies is that etrumadenant does not appear to add significant or unexpected toxicities to those of the backbone therapies with which it is combined.[26] For example, in the ARC-3 study, the safety profile of etrumadenant plus mFOLFOX-6 was consistent with that known for mFOLFOX-6 alone.[26] The most common treatment-emergent adverse events (TEAEs) in that trial were fatigue (70%), thrombocytopenia (57%), diarrhea (52%), and nausea (52%)—all well-recognized side effects of the chemotherapy regimen.[26] Similarly, in the ARC-6 trial in mCRPC, the safety profile of the etrumadenant-based combination was consistent with the known profiles of each individual agent.[36]

5.2. Comparative Safety Insights from Randomized Trials

Data from the large, randomized trials provide a more nuanced understanding of etrumadenant's safety and tolerability relative to standard-of-care or other experimental regimens. A critical observation from the ARC-9 trial in mCRC highlights the difference between the incidence of adverse events and the clinical manageability of a regimen. In that study, the four-drug EZFB arm was associated with a higher rate of Grade ≥3 TEAEs compared to the single-agent regorafenib arm (82.4% vs. 48.6%).[23] This finding is not unexpected, given the known toxicity profiles of the chemotherapy and immunotherapy components of the combination. However, a more clinically relevant measure of tolerability is the rate at which adverse events lead to the cessation of treatment. On this metric, the EZFB regimen performed substantially better: only 5.4% of patients in the etrumadenant arm had to discontinue all study drugs due to TEAEs, compared to 17.1% in the regorafenib arm.[23] This suggests that while the adverse events associated with the combination regimen were more frequent, they were more manageable, allowing a significantly higher proportion of patients to remain on a highly effective therapy for a longer duration. This superior tolerability is a key attribute of the regimen and likely a significant contributor to the dramatic survival benefit observed.

In the ARC-7 trial in NSCLC, the addition of etrumadenant to the domvanalimab/zimberelimab doublet was associated with a modest increase in the incidence of certain immune-related adverse events. The triplet arm showed a higher rate of rash (18%) and infusion-related reactions (10%) compared to the doublet arm (10% and 4%, respectively) and the zimberelimab monotherapy arm (12% and 4%, respectively). However, all reported cases of rash were low-grade (Grade 1-2) and manageable with topical corticosteroids, indicating that these events did not pose a significant safety concern.[30]

VI. Development History and Current Status

6.1. Corporate and Strategic Trajectory

Etrumadenant was discovered and advanced into clinical development by Arcus Biosciences, a U.S.-based biopharmaceutical company focused on creating innovative cancer immunotherapies.[9] The program gained significant momentum and external validation in 2020 through a major strategic partnership with Gilead Sciences. In a multi-program deal, Gilead acquired an option on etrumadenant and other assets in the Arcus pipeline. In 2021, Gilead exercised this option, making a payment of $725 million to secure rights to co-develop and co-commercialize etrumadenant globally, with Arcus retaining rights to royalty payments.[37] This partnership provided substantial financial resources and the expertise of a major pharmaceutical company to advance the late-stage development of the drug.

6.2. Recent Strategic Shifts and Regulatory Outlook

Despite the highly promising clinical data generated in the ARC-9 trial, the development trajectory of etrumadenant took a sharp and unexpected turn in 2025. Following the presentation of the impressive survival data, Arcus Biosciences held discussions with the FDA in March 2025 regarding a potential registration path for the EZFB regimen in third-line mCRC.[47] The outcome of this meeting was reportedly a recommendation from the agency that a new, large-scale, confirmatory Phase 3 trial would be required for approval.[47]

This regulatory feedback appears to have been a pivotal event. A Phase 3 trial represents a massive investment of time and capital, often costing hundreds of millions of dollars and taking several years to complete. Shortly after this regulatory interaction, in June 2025, Gilead Sciences made the strategic decision to terminate its license for etrumadenant and return the full rights to the program back to Arcus Biosciences.[46] Subsequently, in its second-quarter earnings report, Arcus announced a "pause" in the development of etrumadenant.[47]

This sequence of events highlights a critical and challenging reality in modern drug development, often referred to as the "valley of death" between mid-stage and late-stage clinical trials. The exceptional efficacy demonstrated in the Phase 2 ARC-9 trial was, by itself, insufficient to guarantee progression. The FDA's standard and rigorous requirement for Phase 3 confirmation, combined with a commercial and strategic calculation by Gilead—likely weighing the substantial cost, timeline, and potential market return against other priorities in its portfolio—led to the withdrawal of the larger partner. This left Arcus, a smaller biotech company, with a scientifically validated but commercially stranded asset. The "pause" in development is a direct consequence of this complex interplay between promising clinical science, stringent regulatory standards, and the immense financial risks of late-stage oncology development.

VII. Expert Synthesis and Future Perspective

7.1. Integrated Assessment: A Profile of Dichotomy

Etrumadenant embodies a profile of profound dichotomy. On one hand, it is a molecule of significant scientific merit, designed based on a strong biological rationale. Its mechanism as a dual A2a/A2b receptor antagonist has been validated not only preclinically but also at a molecular level within patient tumors, where it was shown to reverse adenosine-driven immunosuppressive gene signatures.[3] This mechanism translated into one of the most impressive efficacy signals seen in recent years for refractory metastatic colorectal cancer, where the etrumadenant-based regimen more than doubled overall survival compared to the standard of care in a randomized Phase 2 trial.[23]

On the other hand, the therapeutic window for this potent immunomodulatory agent appears to be highly context-dependent. The clear lack of differentiated efficacy in metastatic castration-resistant prostate cancer and EGFR-mutated non-small cell lung cancer demonstrates that simply targeting the adenosine pathway is not a universally applicable strategy.[33] The success or failure of etrumadenant is critically dependent on the underlying biology of the tumor and its microenvironment. Factors such as the baseline level of adenosine production (e.g., via CD73 expression), the density and type of immune infiltrate, and the presence of other co-dominant resistance mechanisms likely dictate whether adenosine receptor blockade can successfully tip the balance in favor of an effective anti-tumor immune response.

7.2. Future Outlook

The future of etrumadenant is currently uncertain. The development "pause" represents a significant setback, and restarting a program of this scale is a formidable challenge. The most direct path forward would be to conduct the Phase 3 trial in third-line mCRC as requested by the FDA. However, securing the necessary funding for such a trial will likely require Arcus Biosciences to find a new development partner willing to make a substantial investment based on the strength of the Phase 2 data.

The strong biomarker results from the ARC-9 trial could be instrumental in de-risking such a venture. A future Phase 3 study could be designed to prospectively select patients based on CD73 expression or another biomarker of a highly adenosinergic TME, potentially enriching for a population with a very high likelihood of response and increasing the probability of trial success.[3] Beyond mCRC, the ongoing trials in rectal cancer and sarcomas may yet reveal other indications where the drug's mechanism is highly effective.[39]

Ultimately, the story of etrumadenant serves as a powerful and instructive case study for the field of cancer immunotherapy. It validates the adenosine axis as a legitimate and highly potent therapeutic target. It underscores the critical need for precision medicine approaches, where a deep understanding of tumor biology is used to guide the application of powerful immunomodulatory agents to the right patients. And finally, it illustrates the complex and often unforgiving landscape of drug development, where compelling science and impressive clinical data must still navigate the immense financial and regulatory challenges on the long road from the laboratory to the clinic.

Works cited

  1. ARC-9: Phase Ib/II study to evaluate etrumadenant (AB928)-based treatment combinations in patients with metastatic colorectal cancer (mCRC). - ASCO Publications, accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2021.39.3_suppl.TPS150
  2. R Antagonist Etrumadenant with a Reduced Chemotherapy Regimen Leads to Enhanced Tumor Efficacy and Survival - Arcus Biosciences, accessed September 12, 2025, https://arcusbio.com/wp-content/uploads/2023/10/2023-SITC-etruma-FINAL-ver2.pdf
  3. 52 The adenosine receptor antagonist etrumadenant reduces tumor adenosine-regulated NR4A gene expression and increases mCRC inflammation in patients from the ARC-9 trial - The Journal for ImmunoTherapy of Cancer, accessed September 12, 2025, https://jitc.bmj.com/content/12/Suppl_2/A58?rss=1
  4. ARC-9 - Arcus Biosciences, accessed September 12, 2025, https://arcusbio.com/wp-content/uploads/2021/01/Arcus-ASCO-GI-ARC-9-Poster_FINAL.pdf
  5. Etrumadenant (AB928; AB-928) | dual antagonist of the A2aR and A2bR adenosine receptors| CAS 2239273-34-6 | anticancer and immunomodulatory - InvivoChem, accessed September 12, 2025, https://www.invivochem.com/ab928.html
  6. Definition of etrumadenant - NCI Drug Dictionary, accessed September 12, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/etrumadenant
  7. Etrumadenant | Mechanism of Action - Arcus Biosciences, accessed September 12, 2025, https://arcusbio.com/our-science/clinical-candidates/adenosine-axis/etrumadenant/
  8. ETRUMADENANT - Inxight Drugs, accessed September 12, 2025, https://drugs.ncats.io/substance/W0ZE0NT8IF
  9. Arcus Biosciences - Etrumadenant - AdisInsight - Springer, accessed September 12, 2025, https://adisinsight.springer.com/drugs/800049311
  10. ETRUMADENANT - New Drug Approvals, accessed September 12, 2025, https://newdrugapprovals.org/2020/12/19/etrumadenant/
  11. Etrumadenant: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed September 12, 2025, https://go.drugbank.com/drugs/DB17506
  12. Compound: ETRUMADENANT (CHEMBL4740383) - ChEMBL, accessed September 12, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL4740383
  13. Etrumadenant | CAS 2239273-34-6 | Sun-shinechem, accessed September 12, 2025, https://www.sun-shinechem.com/Details/Etrumadenant/4949/2239273-34-6.html
  14. Etrumadenant (AB928) | Adenosine Receptor antagonist | 99.8%(HPLC) | In Stock, accessed September 12, 2025, https://www.selleckchem.com/products/ab928.html
  15. Etrumadenant | CAS#2239273-34-6 | A2aR and A2bR inhibitor - MedKoo Biosciences, accessed September 12, 2025, https://www.medkoo.com/products/31414
  16. Etrumadenant (AB928; A2aR/A2bR antagonist-1) | CAS 2239273-34-6, accessed September 12, 2025, https://www.abmole.com/products/etrumadenant.html
  17. ARC-19 Lay Summary - Arcus Biosciences Clinical Trials, accessed September 12, 2025, https://trials.arcusbio.com/pdf/ARC-19.pdf
  18. Food and Co-administration of Acid Reducing Agents (ARAs) Have No Clinically Significant Effect on the Pharmacokinetics of Etrumadenant, a Novel Dual Adenosine Receptor Antagonist - Amador Bioscience, accessed September 12, 2025, https://www.amadorbioscience.com/blog/etruma_aras-modeling-ascpt-poster
  19. • Acid reducing agents (PPIs, H2RAs, and Antacids) can be co ..., accessed September 12, 2025, https://arcusbio.com/wp-content/uploads/2024/03/etruma_ara_poster_ascpt2024_final_v3.pdf
  20. AB-928 (CAS Number: 2239273-34-6) | Cayman Chemical, accessed September 12, 2025, https://www.caymanchem.com/product/31444/ab-928
  21. Etrumadenant (AB928) | A2aR/A2bR Antagonist - MedchemExpress.com, accessed September 12, 2025, https://www.medchemexpress.com/etrumadenant.html
  22. An Open Label Study Evaluating the Efficacy and Safety of Etrumadenant (AB928) Based Treatment Combinations in Participants With Metastatic Colorectal Cancer. - Arcus Biosciences Clinical Trials, accessed September 12, 2025, https://trials.arcusbio.com/study/?id=ARC-9
  23. ARC-9: A randomized study to evaluate etrumadenant based ..., accessed September 12, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT455464
  24. ARC-9: A randomized study to evaluate etrumadenant based treatment combinations in previously treated metastatic colorectal cancer (mCRC). - ASCO Publications, accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3508
  25. Gilead and Arcus Announce Etrumadenant Plus Zimberelimab Regimen Significantly Reduced the Risk of Death in Third line Metastatic Colorectal Cancer, accessed September 12, 2025, https://www.gilead.com/news/news-details/2024/gilead-and-arcus-announce-etrumadenant-plus-zimberelimab-regimen-significantly-reduced-the-risk-of-death-in-third-line-metastatic-colorectal-cancer
  26. Arcus Biosciences Presents Updated Data for Etrumadenant in Third-Line Metastatic Colorectal Cancer and New Data on its HIF-2α Program at the AACR 2021 Annual Meeting, accessed September 12, 2025, https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2021/Arcus-Biosciences-Presents-Updated-Data-for-Etrumadenant-in-Third-Line-Metastatic-Colorectal-Cancer-and-New-Data-on-its-HIF-2-Program-at-the-AACR-2021-Annual-Meeting/default.aspx
  27. ARC-9: Phase Ib/II study to evaluate etrumadenant (AB928)-based treatment combinations in patients with metastatic colorectal cancer (mCRC). - ASCO Publications, accessed September 12, 2025, https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.3_suppl.TPS150
  28. Arcus Biosciences Presents Updated Data for Etrumadenant in Third-Line Metastatic Colorectal Cancer and New Data on its HIF-2α, accessed September 12, 2025, https://s202.q4cdn.com/599190870/files/doc_news/Arcus-Biosciences-Presents-Updated-Data-for-Etrumadenant-in-Third-Line-Metastatic-Colorectal-Cancer-and-New-Data-on-its-HIF-2-Program-B8Y4T.pdf
  29. etrumadenant versus zimberelimab in first-line, metastatic, PD-L1-high non-small cell lung cancer (NSCLC). - ASCO, accessed September 12, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT397600
  30. ARC-7: Randomized phase 2 study of domvanalimab + zimberelimab ± etrumadenant versus zimberelimab in first-line, metastatic, PD-L1-high non-small cell lung cancer (NSCLC). - ASCO Publications, accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2022.40.36_suppl.397600
  31. ARC-7 Finds Targeting Both PD-1 and TIGIT in NSCLC Is More Efficacious Than Targeting PD-1 Alone, accessed September 12, 2025, https://dailynews.ascopubs.org/do/arc-7-finds-targeting-both-pd-1-and-tigit-nsclc-more-efficacious-than-targeting-pd-1
  32. Poster # 1309P - Arcus Biosciences, accessed September 12, 2025, https://arcusbio.com/wp-content/uploads/2020/09/ARC-4_ESMO_2020_poster_FINAL.pdf
  33. Arcus Biosciences Provides Update on Clinical Programs, Including Key 2022 Milestones, accessed September 12, 2025, https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2022/Arcus-Biosciences-Provides-Update-on-Clinical-Programs-Including-Key-2022-Milestones/default.aspx
  34. Study Details | NCT04381832 | Adenosine Receptor Antagonist Combination Therapy for Metastatic Castrate Resistant Prostate Cancer | ClinicalTrials.gov, accessed September 12, 2025, https://clinicaltrials.gov/study/NCT04381832
  35. ARC-6: A phase 1b/2, open-label, randomized platform study to evaluate efficacy and safety of etrumadenant (AB928)-based treatment combinations in patients with metastatic castrate-resistant prostate cancer (mCRPC). | Journal of Clinical Oncology - ASCO Publications, accessed September 12, 2025, https://ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.5039
  36. Arcus Biosciences Presents Early Data from ARC-6, a Phase 1b/2 Study Evaluating Etrumadenant-Based Combinations in Metastatic Castrate-Resistant Prostate Cancer at the 2021 ASCO Annual Meeting, accessed September 12, 2025, https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2021/Arcus-Biosciences-Presents-Early-Data-from-ARC-6-a-Phase-1b2-Study-Evaluating-Etrumadenant-Based-Combinations-in-Metastatic-Castrate-Resistant-Prostate-Cancer-at-the-2021-ASCO-Annual-Meeting/default.aspx
  37. Arcus and Gilead terminate development for etrumadenant in prostate cancer, accessed September 12, 2025, https://www.clinicaltrialsarena.com/news/arcus-gilead-terminate-development-etrumadenant-prostate-cancer/
  38. Lack of Clinical Benefit Leads to End of Development for ... - OncLive, accessed September 12, 2025, https://www.onclive.com/view/lack-of-clinical-benefit-leads-to-end-of-development-of-etrumadenant-in-mcrpc
  39. Etrumadenant Recruiting Phase 2 Trials for Rectal Cancer Treatment | DrugBank Online, accessed September 12, 2025, https://go.drugbank.com/drugs/DB17506/clinical_trials?conditions=DBCOND0029030&phase=2&purpose=treatment&status=recruiting
  40. Rectal Cancer Recruiting Phase 2 Trials for Etrumadenant (DB17506) | DrugBank Online, accessed September 12, 2025, https://go.drugbank.com/indications/DBCOND0029030/clinical_trials/DB17506?phase=2&status=recruiting
  41. Etrumadenant Active Not Recruiting Phase 2 Trials for Sarcomas / Dedifferentiated Liposarcoma / Soft Tissue Sarcoma Treatment - DrugBank, accessed September 12, 2025, https://go.drugbank.com/drugs/DB17506/clinical_trials?conditions=DBCOND0044623%2CDBCOND0041813%2CDBCOND0029966&phase=2&purpose=treatment&status=active_not_recruiting
  42. Colorectal Cancers Terminated Phase 1 / 2 Trials for Etrumadenant (DB17506) - DrugBank, accessed September 12, 2025, https://go.drugbank.com/indications/DBCOND0063246/clinical_trials/DB17506?phase=1%2C2&status=terminated
  43. ARC-9: A randomized study to evaluate etrumadenant based treatment combi- nations in previously treated metastatic colorectal cancer (mCRC)., accessed September 12, 2025, https://ascopubs.org/doi/pdf/10.1200/JCO.2024.42.16_suppl.3508
  44. ASCO24: Etrumadenant improves survival in refractory colorectal cancer - Patsnap Synapse, accessed September 12, 2025, https://synapse.patsnap.com/article/asco24-etrumadenant-improves-survival-in-refractory-colorectal-cancer
  45. Etrumadenant by Arcus Biosciences for Metastatic Colorectal Cancer: Likelihood of Approval - Pharmaceutical Technology, accessed September 12, 2025, https://www.pharmaceutical-technology.com/data-insights/etrumadenant-arcus-biosciences-metastatic-colorectal-cancer-likelihood-of-approval/
  46. Gilead hands back one Arcus cancer candidate from $725M deal - Fierce Biotech, accessed September 12, 2025, https://www.fiercebiotech.com/biotech/gilead-hands-back-one-arcus-cancer-candidate-725m-deal
  47. Arcus reaches the end of the road for etrumadenant | ApexOnco - Oncology Pipeline, accessed September 12, 2025, https://www.oncologypipeline.com/apexonco/arcus-reaches-end-road-etrumadenant

Published at: September 12, 2025

This report is continuously updated as new research emerges.

MedPath

Empowering clinical research with data-driven insights and AI-powered tools.

© 2025 MedPath, Inc. All rights reserved.