Ahead of ESMO 2026, the phase III ENERGIZE trial (NCT03661320) is set to add new evidence to the rapidly evolving perioperative treatment landscape of muscle-invasive bladder cancer (MIBC). The study evaluates neoadjuvant chemotherapy alone or in combination with nivolumab, with an additional investigational strategy incorporating the IDO1 inhibitor linrodostat mesylate.
Since ENERGIZE was designed, perioperative immunotherapy has moved forward substantially, changing the context in which its findings will be interpreted. Beyond the clinical results, the trial raises several important immuno-oncology questions: whether chemotherapy-induced tumor antigen release can enhance immune priming, whether the presence of an intact primary tumor matters for systemic antitumor immunity, whether IDO1 inhibition can overcome an additional mechanism of immune resistance, and how dynamic biomarkers such as circulating tumor DNA (ctDNA) could refine treatment selection.
Ahead of the ENERGIZE presentation at ESMO 2026, OncoDaily IO spoke with Guru Sonpavde, MD, about the biological rationale behind the trial and what its findings could add to an increasingly complex perioperative MIBC landscape.
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Why Combine Chemotherapy With Immunotherapy Before Surgery?
The rationale for combining chemotherapy with checkpoint inhibition extends beyond administering two active systemic therapies together. Cytotoxic chemotherapy can induce tumor-cell death and release tumor-associated antigens, potentially increasing antigen availability and facilitating antigen presentation. In the neoadjuvant setting, this occurs while the primary tumor and its associated immune microenvironment remain present.
In principle, checkpoint blockade during this period could facilitate the activation or expansion of tumor-reactive T-cell responses. Whether this mechanism meaningfully contributes to the clinical benefit of perioperative chemoimmunotherapy, however, remains an important translational question.
Dr. Sonpavde explained:
“Yes immunogenic cell death of tumor cells and neoantigen release by chemotherapy with the primary cancer still in the body may prime the immune system for response. Indeed, neoadjuvant combinations of cytotoxic immune checkpoint blockade have already improved outcomes by using the combination of cisplatin, gemcitabine and durvalumab as well as the more robust improvement of outcomes by the combination of enfortumab vedotin (EV) Plus pembrolizumab.”
Positive perioperative trials have made this biological question increasingly relevant. Rather than viewing chemotherapy and checkpoint inhibition simply as independently active treatments, neoadjuvant therapy raises the possibility that treatment-induced tumor-cell death could modify the immune context in which PD-1 blockade acts.
Clinical benefit from a combination, however, does not establish immune priming as the mechanism responsible for that benefit. Translational analyses examining antigen presentation, immune-cell composition, T-cell clonality, and changes within the tumor microenvironment will be needed to determine whether these processes correlate with clinical outcomes. This distinction is particularly important when interpreting mechanistic hypotheses generated by perioperative trials.
ENERGIZE: Testing PD-1 and IDO1 Blockade in Perioperative MIBC
ENERGIZE evaluates neoadjuvant chemotherapy alone or in combination with nivolumab, while an additional investigational strategy incorporates linrodostat mesylate, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1).
The study therefore addresses more than whether checkpoint inhibition can be integrated with chemotherapy. It also examines whether targeting another immunosuppressive pathway could add to PD-1 blockade.
That question is particularly relevant because resistance to checkpoint inhibition is unlikely to depend on a single immune pathway. Even when PD-1 signaling is inhibited, metabolic and cellular mechanisms within the tumor microenvironment may continue to restrict effective antitumor immunity.
Can IDO1 Inhibition Overcome an Additional Layer of Immune Resistance?
IDO1 links tumor metabolism with immune regulation through the tryptophan–kynurenine pathway. Increased IDO1 activity can reduce local tryptophan availability while increasing kynurenine-pathway metabolites, contributing to conditions that may impair effector T-cell activity and favor immunosuppressive cellular programs.
The rationale for combining IDO1 inhibition with PD-1 blockade is therefore mechanistically complementary: PD-1 inhibition attempts to restore checkpoint-constrained T-cell activity, while IDO1 inhibition is intended to interfere with a separate metabolic component of immune suppression.
Dr. Sonpavde explained:
“IDO1 catabolizes tryptophan to kynurenine, depleting tryptophan and generates an immunosuppressive tumor mircoenvironment by upregulating regulatory T cells and myeloid-derived suppressor cells. Hence, IDO1 Inhibition with Linrodostat was intended to overcome this mechanism of resistance to immune checkpoint inhibitor therapy.”
The broader clinical development of IDO1 inhibitors has been challenging, demonstrating that strong biological rationale does not necessarily translate into improved clinical outcomes. This makes the linrodostat component of ENERGIZE scientifically interesting: it evaluates the pathway within a specific context of localized disease, cytotoxic treatment, checkpoint blockade, and an intact primary tumor.
The results will therefore need to distinguish between the biological plausibility of IDO1 inhibition and evidence that targeting the pathway actually adds clinically meaningful benefit.
Does the Intact Tumor Matter for Immune Priming?
Another question raised by neoadjuvant immunotherapy concerns the timing of checkpoint blockade.
Before cystectomy, the primary tumor remains a substantial source of tumor antigens. Treatment-induced tumor-cell death could increase antigen availability while checkpoint inhibition acts on an immune system encountering those antigens in the presence of the tumor and its microenvironment. In principle, this could promote systemic tumor-reactive immunity capable of targeting both the primary lesion and occult micrometastatic disease.
Dr. Sonpavde commented:
“Yes, immunogenic cell death of tumor cells by chemotherapy with the primary cancer still in the body may More optimal than adjuvant therapy. Indeed trials of neoadjuvant cytotoxic therapy immune checkpoint inhibitor therapy have improved overall survival while adjuvant therapy has not clearly improved survival statistically significantly in phase III trials.”
The intact-tumor hypothesis provides a compelling biological rationale for neoadjuvant checkpoint inhibition, but it remains a mechanistic hypothesis rather than an established explanation for clinical benefit.
Differences between neoadjuvant, adjuvant, and perioperative trials cannot be attributed solely to whether the primary tumor is present. Patient populations, systemic treatment backbones, treatment duration, surgical timing, endpoints, and subsequent therapies may all differ. Moreover, studies administering immunotherapy both before and after surgery cannot determine from their primary efficacy results alone how much of the benefit derives from the neoadjuvant versus the adjuvant component.
Translational studies examining the development and persistence of tumor-reactive T-cell populations may therefore be particularly important for understanding whether treatment in the presence of the primary tumor generates a qualitatively different systemic immune response.
Beyond PD-L1: Could ctDNA Better Guide Perioperative Treatment?
As perioperative treatment becomes more effective, identifying which patients require treatment intensification—and which patients are actually benefiting from therapy—becomes increasingly important.
PD-L1 immunohistochemistry provides a baseline measurement of one component of the tumor immune environment, but its predictive value varies according to therapeutic setting. Combination strategies may further limit the ability of baseline PD-L1 expression alone to identify who benefits from perioperative checkpoint inhibition.
ctDNA provides a different type of information because it can be assessed longitudinally. Clearance during systemic therapy may provide a molecular measure of response, while persistence or re-emergence after surgery may identify molecular residual disease before radiographic or clinical recurrence.
Dr. Sonpavde explained:
“ctDNA Molecular residual disease(MRD) clearance appears more informative than PD-L1 IHC to guide perioperative therapy. Combinations of chemo immunotherapy an EV plus pembrolizumab have improved outcomes regardless of PD-L1 IHC. On the other hand, repeated longitudinal ctDNA assessment appears to predict clinical cancer recurrence and adjuvant atezolizumab improved outcomes when administered for postoperative ctDNA detection up to one year after surgery. Moreover, preliminarily, preoperative ctdNA appears to be a better predictor of long term outcomes then pathologic complete remission. Approximately 50 to 60% of patients exhibited ctDNA at baseline in untreated muscle invasive bladder cancer patients, but this information cannot be used at this time to guide the administration of neoadjuvant therapy, and more data are needed.”
The potential value of ctDNA lies in this dynamic dimension. A baseline biomarker describes the disease at one point in time, whereas serial ctDNA may reveal whether molecular disease is disappearing, persisting, or re-emerging during the course of treatment.
An important distinction remains, however, between prognostic, predictive, and treatment-guiding biomarkers. ctDNA may identify patients at particularly high risk of recurrence without necessarily demonstrating which treatment they should receive. Prospective evidence showing improved outcomes from ctDNA-guided escalation or de-escalation will therefore be necessary before it can routinely direct perioperative treatment decisions.
As Dr. Sonpavde emphasizes, baseline ctDNA currently cannot be used alone to determine whether an individual patient should receive neoadjuvant therapy.
Where Does ENERGIZE Fit in the New Perioperative Landscape?
Perhaps the most important context for ENERGIZE at ESMO 2026 is that the MIBC treatment landscape has changed substantially since the study was designed.
Perioperative checkpoint inhibition is no longer being evaluated in a setting with few competing systemic strategies. Positive studies combining checkpoint blockade with cisplatin-based chemotherapy, together with the emergence of enfortumab vedotin plus pembrolizumab, have expanded the therapeutic landscape and shifted the discussion toward how different perioperative approaches should be selected.
Dr. Sonpavde highlighted this changing context:
“Neoadjuvant combinations of cytotoxic immune checkpoint blockade have improved outcomes by using the combination of cisplatin, gemcitabine and durvalumab as well as the combination of enfortumab vedotin (EV) Plus pembrolizumab. Data from the ENERGIZE trial may inform practice, given that there is a choice of 2 perioperative strategies in cisplatin eligible patients.”
This may ultimately be one of the most clinically relevant ways to interpret ENERGIZE.
For cisplatin-eligible patients, treatment selection increasingly involves more than asking whether systemic therapy should be added to surgery. Clinicians need to consider the magnitude and durability of efficacy, toxicity, surgical feasibility, treatment duration, pathological response, long-term survival, patient characteristics, and eventually biomarkers when positioning different perioperative approaches.
Cross-trial comparisons cannot establish which regimen is superior. Differences in eligibility criteria, disease characteristics, treatment backbones, comparator arms, endpoints, and follow-up make indirect ranking unreliable. ENERGIZE should therefore first be interpreted according to its own randomized evidence and then placed within the broader perioperative landscape.
What to Watch at ESMO 2026
The ENERGIZE presentation will be important on several levels.
The first question is whether integrating nivolumab with chemotherapy produces a clinically meaningful improvement and whether any benefit extends beyond pathological response to durable disease control and survival. The magnitude of absolute benefit will be particularly important when the results are considered within a treatment landscape that already contains effective perioperative strategies.
The contribution of linrodostat will also deserve close attention. Given the difficult history of IDO1-directed drug development, evidence that targeting this pathway adds—or does not add—to PD-1 blockade could provide important information about whether metabolic immune suppression remains therapeutically actionable in this setting.
Safety and surgical feasibility will be equally relevant. Any improvement in antitumor efficacy must be considered alongside chemotherapy toxicity, immune-mediated adverse events, treatment discontinuation, delays to cystectomy, and postoperative outcomes.
Finally, biomarker analyses could become particularly informative. PD-L1, ctDNA dynamics, pathological response, and other translational measures may help determine whether benefit is broadly distributed or concentrated within biologically defined populations. As perioperative options expand, understanding who benefits from a particular strategy may become as important as demonstrating benefit in the overall trial population.
