State-of-the-Art Imaging in Antibody-Drug Conjugate Treatment for Advanced Bladder Cancer

Abstract

Antibody-drug conjugates (ADCs) have revolutionized the treatment landscape for advanced bladder cancer, particularly enfortumab vedotin and trastuzumab deruxtecan, which target Nectin-4 and human epidermal growth factor receptor 2 (HER 2), respectively. These ADCs have shown substantial efficacy, improving survival in patients who have progressed after chemotherapy and immunotherapy. Imaging plays a pivotal role in ADC-based therapy, extending beyond diagnosis and staging to assessing treatment response, detecting recurrence, and evaluating toxicity. Computed tomography (CT), multiparametric magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG-PET) are widely used for these purposes. Despite the efficacy of ADCs, resistance mechanisms such as antigen loss and payload resistance continue to pose challenges, necessitating the development of next-generation ADCs. Response assessment largely relies on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, with growing interest in multiparametric MRI for evaluating complete response in bladder lesions. Additionally, imaging helps identify ADC-related toxicities, including pneumonitis and gastrointestinal complications. Radiologists must be aware of these evolving therapeutic and imaging paradigms to optimize patient management. The integration of imaging with ADC-based treatment requires a multidisciplinary approach to improve outcomes. This review highlights the critical role of imaging in ADC therapy and underscores the need for radiologists to adapt to these advancements in bladder cancer treatment.

INTRODUCTION

The rising incidence of bladder cancer globally has imposed significant burdens on patients and healthcare systems [1]. Notably, advanced bladder cancer, including unresectable or metastatic stage IV disease, poses considerable medical and financial challenges, as it is a significant cause of mortality among affected patients and demands substantial healthcare resources. Fortunately, recent advances in antibody-drug conjugates (ADCs) have improved response rates and overall survival in patients with advanced bladder cancer. ADCs are often referred to as “smart chemotherapy” because they combine the tumor-targeting precision of monoclonal antibodies with the potent cytotoxicity of chemotherapy, enabling selective tumor cell killing while minimizing systemic toxicity. ADCs have achieved clinical success in several cancers, including bladder, breast, lung, and lymphoma [2].

ADC-based treatments, with or without immune checkpoint inhibitors (ICIs), represent a pivotal advancement in the therapeutic landscape of advanced bladder cancer, particularly for patients who have progressed after platinum-based chemotherapy and immunotherapy [3,4]. ADCs, such as enfortumab vedotin, which targets Nectin-4, and trastuzumab deruxtecan, which targets human epidermal growth factor receptor 2 (HER 2), have demonstrated significant clinical efficacy in large-scale trials. These include the EV-301 and EV-302 trials for enfortumab vedotin and the DESTINY-PanTumor02 trial for trastuzumab deruxtecan, leading to their United States Food and Drug Administration (FDA) approval for the treatment of urothelial carcinoma [5,6].

State-of-the-art technologies, such as computed tomography (CT) urography, multiparametric MRI (mpMRI), and fluorodeoxyglucose (FDG) positron emission tomography (PET), have long been essential in managing bladder cancer [7]. As ADCs become integrated into clinical practice as key therapeutic options, imaging plays an increasingly critical role in assessing treatment response and detecting recurrence [8]. Additionally, toxicity evaluations have become increasingly important, given imaging’s role in monitoring potential adverse effects [9]. Therefore, radiologists should be aware of response patterns and potential toxicities during ADC-based treatment and apply imaging techniques to assess these factors accurately.

ADC for Bladder Cancer

Mechanism of Action

ADCs represent an innovative and promising class of targeted cancer therapies [6]. They consist of three essential components: a monoclonal antibody, a cytotoxic payload, and a linker that connects the antibody to the payload. The monoclonal antibody is designed to target antigens overexpressed on tumor cells. Upon binding, the ADC is internalized into the cancer cell, where the cytotoxic agent is released, typically after cleavage of the linker within the acidic environment of the lysosome (Fig. 1). This results in targeted cell death while minimizing systemic exposure to the chemotherapeutic agent. This targeted approach allows for the direct delivery of chemotherapeutic agents to cancer cells, potentially improving efficacy and reducing systemic toxicity compared to conventional chemotherapy.

Fig. 1. Structure and mechanism of action of ADCs. An ADC is composed of three main components: a mAb, a chemical linker, and a cytotoxic payload. Upon binding to its target antigen on the tumor cell surface, such as Nectin-4 or Trop-2, the ADC-antigen complex is internalized via receptor-mediated endocytosis. Once internalized, the ADC is trafficked to the lysosome, where the linker is cleaved during lysosomal degradation. This cleavage releases the cytotoxic payload, which then induces DNA damage or disrupts microtubules, ultimately leading to target cell death. The cytotoxic payload may also diffuse from the lysed cell to affect neighboring antigen-negative cells, contributing to additional tumor cell death. ADC = antibody-drug conjugate, mAb = monoclonal antibody.

Enfortumab vedotin (Padcev^®) is the first ADC approved by the U.S. FDA for the treatment of advanced urothelial carcinoma. Nectin-4 is a transmembrane cell adhesion molecule involved in cellular adhesion, migration, and proliferation. While Nectin-4 expression is low in most normal tissues, it is highly overexpressed in urothelial carcinoma, making it an attractive target for ADC therapy. The cytotoxic payload of enfortumab vedotin is monomethyl auristatin E (MMAE), a potent microtubule polymerization inhibitor that induces apoptosis in dividing cells by disrupting mitotic spindle formation. Upon binding to Nectin-4, enfortumab vedotin is internalized and trafficked to lysosomes, where MMAE is released, leading to tumor cell death [5,6].

Sacituzumab govitecan (Trodelvy^®) is an ADC targeting Trop-2, a transmembrane glycoprotein overexpressed in various epithelial cancers, including urothelial, breast, lung, and pancreatic cancers. Sacituzumab govitecan consists of an anti-Trop-2 monoclonal antibody linked to SN-38, the active metabolite of irinotecan, a topoisomerase I inhibitor [6].

Trastuzumab deruxtecan (Enhertu^®) is an ADC targeting HER2. It is composed of trastuzumab, a HER2-targeting monoclonal antibody that selectively binds to HER2-expressing cancer cells, and deruxtecan (DXd), a topoisomerase I inhibitor payload, which is a cytotoxic agent designed to damage DNA and induce cancer cell death [5].

ADC in the Standard of Care

Following FDA approval, enfortumab vedotin and sacituzumab govitecan have been rapidly integrated into clinical practice guidelines, including those from the National Comprehensive Cancer Network^® (NCCN^®) and the European Society for Medical Oncology (ESMO) [10,11].

Enfortumab vedotin received FDA approval in 2019 for the treatment of locally advanced or metastatic urothelial carcinoma in adults previously treated with platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor [12]. In 2021, the FDA approved enfortumab vedotin as a first-line treatment for patients who were ineligible for cisplatin-containing chemotherapy and had previously received a PD-1 or PD-L1 inhibitor. In the same year, the FDA granted accelerated approval to sacituzumab govitecan for patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor [13]. However, in October 2024, sacituzumab govitecan was voluntarily withdrawn for patients with locally advanced or metastatic urothelial carcinoma based on results from the Phase III TROPiCS-04 trial, which did not meet its primary endpoint of overall survival compared to standard chemotherapy [14]. Trastuzumab deruxtecan received accelerated approval from the FDA in April 2024 for the treatment of adults with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who had received prior systemic therapy and had no satisfactory alternative treatment options. This tumor-agnostic approval was based on the DESTINY-PanTumor02 trial [5].

The principles of systemic therapy for locally advanced or metastatic bladder cancer in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for bladder cancer, version 1.2025, are presented in Table 1 [10]. Enfortumab vedotin is included as a primary treatment option across multiple lines of therapy, including first-line treatment in combination with pembrolizumab for both platinum-eligible and ineligible patients, as well as in second- and later-line settings. Trastuzumab deruxtecan is considered useful in selected cases of HER2-positive (IHC 3+) bladder cancer in the subsequent-line setting. In this evolving paradigm, oncologists and urologists are increasingly adopting ADC-based regimens, either alone or in combination [15].

Table 1. Principles of systemic therapy for locally advanced or metastatic bladder cancer.

		Cisplatin eligible	Cisplatin ineligible
First-line systemic therapy
	Preferred regimens	- Pembrolizumab and EV (category 1)	- Pembrolizumab and EV (category 1)
	Other recommended regimens	- Gemcitabine and cisplatin (category 1) followed by avelumab maintenance (category 1) - Nivolumab, gemcitabine, and cisplatin (category 1) followed by nivolumab maintenance therapy (category 1)	- Gemcitabine and carboplatin followed by avelumab maintenance (category 1)
	Useful under certain circumstances	- DDMVAC with growth factor support (category 1) followed by avelumab maintenance (category 1)	- Gemcitabine - Gemcitabine and paclitaxel - Ifosfamide, doxorubicin, and gemcitabine - Pembrolizumab - Atezolizumab (category 2B)
		Post-platinum or other chemotherapy	Post-checkpoint inhibitor
Second-line systemic therapy
	Preferred regimen	- Pembrolizumab (category 1 post-platinum) - Nivolumab - Avelumab - Erdafitinib (FGFR3 alteration) - EV	For cisplatin ineligible, chemo-naïve - EV - Gemcitabine and carboplatin - Erdafitinib (FGFR3 alteration) For cisplatin eligible, chemo-naïve - Gemcitabine and cisplatin - DDMVAC with growth factor support - Erdafitinib (FGFR3 alteration)
	Other recommended regimens	- Paclitaxel or docetaxel - Gemcitabine - Pembrolizumab and EV (category 2B)	- Paclitaxel or docetaxel - Gemcitabine
	Useful under certain circumstances	- Ifosfamide, doxorubicin, and gemcitabine - Gemcitabine and paclitaxel - Gemcitabine and cisplatin - DDMVAC with growth factor support	- Ifosfamide, doxorubicin, and gemcitabine - Gemcitabine and paclitaxel
Subsequent-line systemic therapy
	Preferred regimen	- EV (category 1) - Erdafitinib (category 1)
	Other recommended regimens	- Sacituzumab govitecan - Gemcitabine - Paclitaxel or docetaxel - Ifosfamide, doxorubicin, and gemcitabine - Gemcitabine and paclitaxel - Gemcitabine and cisplatin - DDMVAC with growth factor support
	Useful under certain circumstances	- Trastuzumab deruxtecan (HER2-positive, IHC 3+)

EV = enfortumab vedotin, DDMVAC = dose dense methotrexate, vinblastine, doxorubicin, cisplatin, FGFR3 = fibroblast growth factor receptor 3, HER2 = human epidermal growth factor receptor 2, IHC = immunohistochemistry

Current Challenges and Ongoing Development of ADC-Based Therapy

Bladder cancer resistance and recurrence after ADC-based treatment remain significant challenges, similar to those encountered with other cancer therapies (Fig. 2). For example, bladder cancer cells can develop resistance through antigen loss, which prevents ADCs from recognizing and binding to tumor cells. Antigen loss mechanisms include downregulation of surface target antigens such as Nectin-4 or HER2, and mutations in antigen-binding sites. Additionally, bladder cancer cells may accelerate ADC clearance, enhance payload efflux mechanisms, or alter payload targets, thereby diminishing the therapeutic impact of ADCs [16].

Fig. 2. Mechanisms of resistance to ADCs. There are two primary categories of resistance mechanisms to ADC therapy: antigen loss and payload resistance. Antigen loss mechanisms include down-regulation of the target antigen on tumor cells, reducing ADC binding, and mutations in the antigen-binding site that prevent effective recognition by the monoclonal antibody. Payload resistance mechanisms include clearance of ADCs before payload release, efflux of the payload from the cell via drug efflux pumps, and alterations in the payload's intracellular target that inhibit its ability to induce cell death. ADC = antibody-drug conjugate.

Concurrently, new ADCs are under development to overcome these resistance and recurrence mechanisms by refining target selection and optimizing payloads [17]. For example, novel ADCs such as tisotumab vedotin (targeting tissue factor) and disitamab vedotin (targeting HER2) are being evaluated in clinical trials for patients with metastatic urothelial cancer [18,19].

In addition, clinical trials are exploring the use of ADCs in the neoadjuvant setting. For instance, disitamab vedotin in combination with tislelizumab, a PD-1 inhibitor, is being investigated as a novel neoadjuvant regimen for patients with HER2-positive locally advanced muscle-invasive bladder cancer (MIBC), demonstrating encouraging preliminary results in terms of clinical complete response (CR) and bladder-sparing potential [20,21].

Role of Imaging for ADC-Based Therapy

Imaging Modalities for Bladder Cancer

Imaging provides crucial insights into diagnosis, staging, assessment of treatment response, and surveillance of bladder cancer. Among these uses, the number of CT or MRI scans performed for treatment response assessment and surveillance significantly exceeds those conducted for diagnosis and staging. Approximately 5%–10% of patients present with metastatic disease at diagnosis, and recurrence after radical cystectomy occurs locally in 30%, with distant metastases developing in up to 50% of patients [10,17].

CT is the most accessible and commonly used imaging modality for multisystem assessment in bladder cancer. In patients with non MIBC (NMIBC), routine CT surveillance is generally not required and is recommended only when symptoms or risk factors are present. For MIBC, CT surveillance after treatment is standard practice [11,22]. CT urography (CTU), also known as a CT urogram, and contrast-enhanced scans are typically employed. Recent advancements in computerized volume analysis, such as the auto-initialized cascaded level set system, have shown promising results for 3D segmentation of bladder tumors, providing more accurate assessments of tumor volume changes compared to traditional criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [23,24].

MRI, with its superior soft-tissue resolution, is more reliable than CT for the detailed evaluation of primary bladder cancer, particularly in assessing muscle invasion during staging and evaluating treatment response during systemic therapy [25]. The use of mpMRI, which incorporates T2-weighted, diffusion-weighted, and dynamic contrast-enhanced imaging, has further enhanced the role of MRI in bladder cancer diagnosis and treatment assessment [3]. Currently, the Vesical Imaging-Reporting and Data System (VI-RADS), proposed by the European Association of Urology, facilitates mpMRI for bladder cancer diagnosis and staging and standardizes reporting [26]. In addition, MR urography (MRU), also known as MR urogram, is recommended for detailed evaluation of the upper urinary tracts for synchronous or metachronous lesions.

FDG-PET/CT is a sensitive imaging modality for detecting FDG-avid malignant disease. However, its use in bladder cancer remains debated due to the high urinary excretion of FDG, which limits the evaluation of the bladder wall and ureters [27]. Currently, FDG-PET/CT is used for evaluating metastatic disease when metastasis is suspected, although other modalities are preferred [10].

Imaging Strategy in the Standard of Care

The NCCN guidelines for advanced or metastatic bladder cancer recommend various imaging strategies based on the clinical scenario (Table 2) [10]. For MIBC staging, chest imaging with CT scans or chest X-rays is recommended, along with abdominal and pelvic imaging using CTU or MRU. For follow-up after cystectomy, chest imaging with CT and abdominal/pelvic imaging with CTU or MRU is recommended every 3–6 months for 2 years, followed by annual chest CT plus abdominal/pelvic CT/MRI for up to 5 years to detect recurrence. For metastatic disease, a CT of the chest, abdomen, and pelvis is recommended every 3–6 months, with any clinical change or new symptoms, to assess treatment response. FDG-PET/CT can be utilized when metastasis is suspected.

Table 2. Principles of imaging for advanced or metastatic bladder cancer.

Purpose	Imaging strategy
Staging for MIBC	• Chest imaging
		- CT of the chest with or without contrast (preferred)
		- PA and lateral chest X-ray
	• Abdomen/pelvis imaging
		- CTU (CT of the abdomen and pelvis without and with contrast with excretory imaging)
		- MRU for patients with poor renal function or contrast allergy (but with GFR >30 and no acute failure)
		- Renal ultrasonography and CT without contrast for those who cannot receive any contrast agents
		- MRI of the pelvis may be performed in addition to CTU
	• FDG-PET/CT (category 2B)
		- in selected patients with ≥cT2 disease
Follow-up with or without cystectomy for MIBC	• Chest imaging
		- Chest CT (preferred) or chest X-ray every 3–6 months for 2 years, then annually for up to 5 years
	• Abdomen/pelvis imaging
		- CTU or MRU every 3–6 months for 2 years, then abdomen/pelvis CT or MRI annually for up to 5 years
	• FDG-PET/CT (category 2B)
		- In patients with high-risk MIBC if metastasis is suspected
Follow-up for metastatic disease	• Chest and abdomen imaging
		- CT chest/abdomen/pelvis Chest CT every 3–6 months with any clinical change or new symptoms, which can be modified according to systemic therapy or surveillance plan
		- CTU or MRU every 3–6 months as abdomen/pelvis imaging if clinically indicated and with any clinical change or new symptoms
	• FDG-PET/CT (category 2B)
		- If metastasis is suspected
Evaluation for suspected bone metastasis	• Patients at high risk or with symptoms or laboratory indicators of bone metastasis may be imaged with MRI, FDG-PET/CT (category 2B), or bone scan. FDG-PET/CT (category 2B) may also be considered for cases of suspected extraosseous metastases
Neurologic/brain imaging	• Brain MRI without and with contrast for symptomatic or high-risk (e.g., small cell histology) patients. CT with contrast is considered only when MRI is contraindicated (e.g., non-MRI-compatible devices or foreign body)

MIBC = muscle invasive bladder cancer, CT = computed tomography, PA = posteroanterior, CTU = CT urography, MRU = MR urography, GFR = glomerular filtration rate, MRI = magnetic resonance imaging, FDG = fluorodeoxyglucose, PET = positron emission tomography

In routine clinical practice, imaging assessments generally follow institutional protocols and typically use structured report templates. However, the interpretation of treatment response, whether progression, stability, or response, is primarily dependent on the radiologist’s judgment, often based on comparison with the most recent prior imaging rather than a formal baseline comparison. Recently, the neoadjuvant chemotherapy VI-RADS (nacVI-RADS), a five-point scoring system initially proposed for chemotherapy, has now been applied to evaluate radiologic response to neoadjuvant immunotherapy using mpMRI in patients with MIBC. In this system, scores of 1–2 indicate complete radiologic response (Supplementary Fig. 1), 3 suggests downstaging to NMIBC, 4 indicates partial response (PR) with residual MIBC, and 5 reflects no response or progressive disease. The nacVI-RADS is expected to enhance the accuracy and reproducibility of imaging-based response assessment in MIBC following neoadjuvant immunotherapy [28].

Imaging Strategy in Clinical Trials

In cancer clinical trials, imaging strategies are rigorously standardized according to U.S. FDA clinical trial imaging endpoint standards [29]. The imaging modality and assessment frequency must be clearly specified in the trial protocol and applied uniformly throughout the study period. While the imaging modalities used are generally similar to those in routine clinical care, imaging is often performed more frequently. For example, in a phase I study of single-agent enfortumab vedotin, CT scans were performed every 8 weeks [30].

Response assessment is typically based on formal criteria such as RECIST 1.1 or Irecist, and image comparisons are consistently performed against the defined baseline scan. Additionally, image evaluations are often conducted by blinded independent central review panels to ensure objectivity and consistency, which contrast with the more subjective, real-time assessments in standard clinical workflows.

Imaging for Treatment Response Assessment

Currently, most evidence supporting the efficacy of ADC-based therapies originates from clinical trials, as real-world data remain limited due to the short period since their approval [31]. Both ADC monotherapy and combination therapy with pembrolizumab have demonstrated promising outcomes in patients with locally advanced or metastatic urothelial carcinoma. There is no substantial difference in imaging response patterns between ADC-based regimens and conventional chemotherapy (Supplementary Fig. 2). However, ADCs generally demonstrate higher objective response rates (ORRs) and more pronounced tumor shrinkage in responsive patients.

In the EV-201 trial, enfortumab vedotin monotherapy showed a confirmed ORR of 51.7% (46 of 89), with 20.2% (18 of 89) CRs and 31.5% (28 of 89) PRs in cisplatin-ineligible patients previously treated with programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors [32]. In the EV-301 trial, the ORR was 40.6% (117 of 288), with 4.9% (14 of 288) CRs in patients who had received platinum-based treatment and a PD-1 or PD-L1 inhibitor [33]. The combination of enfortumab vedotin and pembrolizumab demonstrated superior responses compared to monotherapy in the EV-302 trial, with a confirmed ORR of 67.7% and 29.1% CRs in patients with untreated locally advanced or metastatic urothelial carcinoma [34].

Although sacituzumab govitecan monotherapy showed an ORR of 27.7%, with 5.4% CRs and 22.3% PRs in the TROPHY-U-01 trial [35], it did not result in a significant improvement in overall survival compared to treatment of physician’s choice (10.3 months vs. 9.0 months; hazard ratio 0.86) or progression-free survival (4.2 months and 3.6 months; hazard ratio 0.86) in pretreated advanced urothelial carcinoma in the TROPiCS-04 phase III randomized trial [14].

Trastuzumab deruxtecan achieved an ORR of 39.0% in bladder cancer across all HER2 expression levels. Patients with high HER2 expression (IHC 3+) demonstrated a significantly higher ORR of 56.3%, suggesting that HER2 expression levels may influence treatment efficacy, as shown in the phase II DESTINY-PanTumor02 trial [5].

There are several issues worth discussing regarding treatment response assessment on imaging. The first is the response criteria for ADC-based therapy. All these clinical trials used RECIST 1.1 for response assessment [32,33,34,35]. While RECIST 1.1 has been a well-established assessment method for over 15 years, it is known to have limitations in evaluating responses to immunotherapy due to pseudoprogression, which led to the development of immune-specific response criteria such as iRECIST [8]. However, pseudoprogression has been reported to be very rare in urothelial carcinoma [36]. Therefore, pseudoprogression may not need to be considered when assessing treatment response on imaging, and RECIST 1.1 remains a reliable criterion for advanced bladder cancer treated with ADC-based therapy. Given that pseudoprogression occurs due to early immune cell infiltration following initial monotherapy administration, it does not need to be considered in cases where ADCs are combined with immunotherapy, such as the combination of pembrolizumab and enfortumab vedotin as first-line palliative treatment.

The second issue is assessing CR in primary bladder cancer on imaging. The urinary bladder is a dynamic organ with varying degrees of distension depending on urine volume, which can complicate the detection and measurement of primary bladder cancer. Post-treatment scar tissue from a primary bladder tumor may present as mild bladder wall thickening on CT or MRI, potentially leading radiologists to incorrectly assess a PR instead of a CR, even when cystoscopy or pathology confirms a CR. Indeed, a study exploring organ-specific response in bladder cancer patients treated with enfortumab vedotin reported a CR rate of 0% for primary bladder cancer. In contrast, CR rates were 5.5%, 29.4%, and 18.2% for lymph node metastases, lung metastases, and liver metastases, respectively, where tumor measurement is easier and more reliable [31]. To address the inherent limitations of bladder evaluation on CT/MRI, mpMRI has been investigated for assessing response to neoadjuvant therapy [37]. This approach combines T1 or T2-weighted sequences for anatomical evaluation, diffusion-weighted imaging for functional assessment, and dynamic contrast-enhanced imaging to evaluate early perfusion characteristics. For example, dense T2 hypointensity without diffusion restriction of the bladder lesion may represent a CR (Fig. 3).

Fig. 3. A 57-year-old man with locally advanced bladder cancer treated with enfortumab vedotin. A: Baseline axial MRI shows a protruding bladder wall thickening in the left posterior bladder wall (arrows) with T2 hypointensity and diffusion restriction on the DWI and ADC map. B: MRI at 6 months after starting treatment demonstrates a substantial reduction in the size of the bladder wall thickening (arrows), with dense T2 hypointensity without diffusion restriction on DWI and the ADC map. MRI = magnetic resonance imaging, DWI = diffusion-weighted image, ADC = apparent diffusion coefficient, WI = weighted image.

The third Issue is assessing bone metastases response. Bone metastases frequently occur in the pelvic bones and spine [38]. While bone metastases from urothelial carcinoma are often osteolytic, osteoblastic lesions can also be observed [39]. In some cases, discordant responses to systemic therapy are seen on CT or MRI between bone metastases and metastases in other organs (Fig. 4). Additionally, patients with bone metastases may experience skeletal-related events, such as pathological fractures, which can hamper response assessment on conventional abdominal or pelvic CT or MRI. Therefore, the NCCN guidelines recommend bone-specific imaging, such as bone scans, musculoskeletal MRI, or FDG-PET/CT, for evaluation [10].

Fig. 4. A 60-year-old man with metastatic bladder cancer treated with enfortumab vedotin. A: Baseline axial contrast-enhanced CT shows osteolytic metastasis in the right rib (arrow) and bilateral hilar lymph node metastases (arrowheads). B: CT scan at 4 months after starting treatment shows an increased size of osteolytic right rib metastasis (arrow) with decreased size of the bilateral hilar lymph node metastases (arrowheads). CT = computed tomography.

Imaging for Toxicity Evaluation

ADCs are targeted therapies designed to selectively deliver potent cytotoxic agents to cancer cells while minimizing damage to healthy tissues. Despite their targeted mechanism, ADCs can still cause significant toxicities arising from both the antibody component (immune-related effects) and the cytotoxic payload (chemical-related toxicities) [6]. As a result, certain ADC-related complications may resemble immune-related adverse events observed with ICIs, while others may differ in nature and, in some cases, present with greater severity [9].

Toxicities typically arise from two primary mechanisms: off-target toxicity and on-target, off-site toxicity. Off-target toxicity refers to adverse effects caused by the unintended release of the cytotoxic payload in areas of the body outside target cancer cells. Early premature release of the payload into the bloodstream can cause damage to hematologic cells, leading to neutropenia, anemia, and thrombocytopenia; lung alveolar and endothelial cells, causing pneumonitis; liver cells, resulting in hepatotoxicity; and neurons, leading to peripheral neuropathy [40].

On-target, off-site toxicity occurs when an ADC binds to normal cells that express the target antigen, leading to toxicity in normal tissue such as the skin, eye, and gastrointestinal mucosa [40]. Dermatologic and ocular toxicities are common on-target, off-site toxicities with enfortumab vedotin but are rare in patients treated with sacituzumab govitecan [13].

Different toxicity profiles are observed across ADCs, related to the antibodies and payloads used (Table 3). Reike et al. [40] reported that dermatologic (38.6%) and neurologic (16.5%) toxicities are common with enfortumab vedotin, while gastrointestinal toxicity (24.2%) is more frequent with sacituzumab govitecan. Yoon et al. [41] reported that enfortumab vedotin-related pneumonitis was more common than expected, occurring in 28% of patients (all grades) and in 6.25% of patients with grade 3 to 5 toxicity, based on a retrospective review.

Table 3. Toxicities of EV and SG.

Toxicity	EV	SG	Notes
Peripheral neuropathy	Common, frequently severe (grade 3 or higher)	Less common	Off-target toxicity of EV due to MMAE
Dermatologic toxicity	Very common: rash, pruritus, severe reactions like SJS/TEN	Rare	On-target, off-site toxicity of EV due to Nectin-4 expression in skin for EV
Hematologic toxicity	Less common: neutropenia, anemia	Very common: neutropenia, anemia, thrombocytopenia	Off-target toxicity of SG due to SN-38 (active metabolite of irinotecan)
Gastrointestinal toxicity	Less common: diarrhea, nausea	Common: diarrhea, nausea, vomiting	Off-target toxicity of SG due to SN-38 (active metabolite of irinotecan)
Ocular toxicity	Common: dry eyes, blurred vision	Rare	On-target, off-site toxicity of EV due to Nectin-4 expression in ocular tissues
Hepatotoxicity	Common: mild elevations in liver enzymes	Less common: mild elevations in liver enzymes	Off-target toxicity of EV and SG
Pneumonitis	Less common	Less common	Off-target toxicity of EV and SG

EV = enfortumab vedotin, SG = sacituzumab govitecan, MMAE = monomethyl auristatin E, SJS/TEN = Stevens-Johnson syndrome/toxic epidermal necrolysis

In a meta-analysis, trastuzumab deruxtecan was associated with interstitial lung disease/pneumonitis in 12.5% of patients, with grade 3 to 5 severity in 2.2%, requiring close monitoring and corticosteroid treatment if detected. Hematologic toxicities included neutropenia (36.4%), anemia (36.8%), and thrombocytopenia (26.8%), which may necessitate dose adjustments or supportive care. Gastrointestinal adverse effects such as nausea (70.7%), vomiting (37.2%), and diarrhea (29.1%) are common but manageable with antiemetics and hydration, while fatigue is another frequent adverse effect (41.0%) [42].

Of these toxicities, imaging is often used to diagnose pneumonitis and gastrointestinal toxicity. Pneumonitis patterns on CT can be classified according to the American Thoracic Society/European Respiratory Society classification [43]. In the study by Yoon et al. [41], the CT patterns of enfortumab vedotin-related pneumonitis included organizing pneumonia (66.7%), followed by non-specific interstitial pneumonia (16.7%), unclassifiable patterns (11.1%), and hypersensitivity pneumonitis (5.6%). At our institution, the majority of enfortumab vedotin-related pneumonitis cases have exhibited a mild organizing pneumonia pattern (Fig. 5). The median time from initiation of enfortumab vedotin to the onset of pneumonitis has been reported as 13.1 weeks [41]. ADC-related pneumonitis is often treated with steroids and is mostly reversible.

Fig. 5. Drug-induced pneumonitis in patients treated with enfortumab vedotin. A-C: Chest computed tomography scans of a 60-year-old man at 2 months after starting treatment (A), a 52-year-old man at 3 months after starting treatment (B), and a 64-year-old man at 2 years after starting treatment (C) demonstrate multifocal nodular ground-glass opacities (arrows) and consolidation (arrowhead).

In patients with gastrointestinal toxicity, the commonly observed CT findings include fluid-filled and dilated bowel loops with mild bowel wall thickening (Fig. 6) [44]. Rarely, superimposed enterocolitis, such as neutropenic enterocolitis, may occur, which shows edematous bowel wall thickening and adjacent fat stranding on CT [45].

Fig. 6. A 61-year-old man with bladder cancer treated with enfortumab vedotin. Axial contrast-enhanced CT scan at 2 months starting treatment, CT shows fluid-filled and dilated colon (arrows) and mild colon wall thickening (arrowhead). CT = computed tomography.

Role of Radiologists

Radiologists should be part of multidisciplinary teams alongside medical oncologists, surgeons, and radiation oncologists to optimize care for patients with advanced bladder cancer. They should have a clear understanding of the clinical questions at hand and the role of imaging at each stage (Table 4). It is crucial for radiologists not only to be familiar with the imaging findings of primary bladder tumors and patterns of metastasis but also to understand the mechanisms of ADCs and the imaging findings related to treatment response and toxicity, particularly with current ADC-based therapies. Currently, enfortumab vedotin combined with pembrolizumab is used as first-line systemic therapy for advanced bladder cancer, and toxicity may occur from pembrolizumab as well. The response patterns and toxicities of pembrolizumab have been extensively investigated [46,47,48]. Additionally, providing feedback to oncologists regarding the concordance between imaging and clinical findings is of paramount importance.

Table 4. Radiology related issues for ADC-based treatment in patients with locally unresectable or metastatic bladder cancer.

Clinical questions	What radiologists need to know
Which imaging modalities should be primarily ordered for screening or baseline imaging before ADC-based treatment?	- In the NCCN guidelines, both CT and MRI are recommended for evaluating primary bladder cancer and metastatic disease
	- Chest/abdomen/pelvis CT remains a key modality, and if a more detailed evaluation of bladder cancer is needed, either CT abdomen/pelvis using a CT urography protocol can be utilized
	- FDG-PET/CT is also recommended (category 2B)
Which imaging modalities should be performed for patients with suspected bone or brain metastasis?	The NCCN guidelines recommend FDG-PET/CT or bone scan for bone metastasis, and brain MRI without/with contrast for brain metastasis in both screening and follow-up (category 2B)
Which response criteria should be used for clinical trial?	RECIST 1.1 is enough, as pseudoprogression has been reported very rarely in urothelial carcinoma
How to differentiate CR and PR on imaging?	CR rate is a critical endpoint in some clinical trial. When primary bladder cancer is resolved, remaining scar tissue may hamper to determine CR. Multiparametric MRI might be helpful. For example, dense T2 hypointensity without diffusion restriction of the bladder lesion may represent CR
How can we diagnose pneumonitis on CT?	Pneumonitis can be detected and classified on CT according to ATS/ERS classification. The most common pattern of EV or SG-related pneumonitis is organizing pneumonia. Frequently, clinical correlation is required to differentiate drug-related pneumonitis and infectious pneumonia
How can we use CT for gastrointestinal toxicity?	When patients show severe diarrhea along with abdominal pain and laboratory abnormalities, abdominal CT can be used to evaluate any superimposed enterocolitis

ADC = antibody-drug conjugate, NCCN = National Comprehensive Cancer Network, CT = computed tomography, MRI = magnetic resonance imaging, FDG = fluorodeoxyglucose, PET = positron emission tomography, RECIST = Response Evaluation Criteria in Solid Tumors, CR = complete response, PR = partial response, ATS/ERS = American Thoracic Society/European Respiratory Society, EV = enfortumab vedotin, SG = sacituzumab govitecan

Conclusion

The diagnosis and management of patients with locally advanced and metastatic bladder cancer have evolved and will continue to change. Currently, ADC-based therapy, with or without ICIs, has dramatically improved overall survival in patients with advanced bladder cancer. These improvements in care compel radiologists to remain knowledgeable about the mechanisms of ADCs, the utility of imaging modalities for advanced bladder cancer, treatment response patterns, and imaging-based toxicity findings related to ADC-based therapy.

Supplement

The Supplement is available with this article at https://doi.org/10.3348/kjr.2025.0416.