Enhanced Bladder Cancer Outcomes Stem From Individualized First-Line Regimens

Chandler Park, MD, FACP

Treatment decision-making for patients with previously untreated bladder cancer requires a comprehensive understanding of how each of the available regimens would perform in individual patients based on factors including age, ECOG performance status, and cisplatin eligibility, according to Chandler Park, MD, FACP.

“The [National Comprehensive Cancer Network] category 1 treatment options we have today [for patients with treatment-naive bladder cancer are]: enfortumab vedotin-ejfv [Padcev] plus pembrolizumab [Keytruda], cisplatin and gemcitabine plus nivolumab [Opdivo]—as long as patients are cisplatin eligible, and cisplatin or carboplatin with gemcitabine for 4 to 6 cycles, [followed by] maintenance avelumab [Bavencio] immunotherapy,” Park said in an interview with OncLive®.

In the interview, Park—a medical oncologist at Norton Cancer Institute in Louisville, Kentucky—discussed optimal clinical scenarios for the use of the FDA-approved 3 first-line treatment options for patients with bladder cancer, patient characteristics that influence his treatment decision-making, the importance of molecular markers, and emerging therapies.

OncLive: What standard first-line treatment options do you typically consider for patients with bladder cancer?

Park: We’re fortunate as oncologists who treat patients with bladder cancer. Approximately 20 years ago, the life expectancy for a patient with [treatment-naive] metastatic bladder cancer was approximately 9 to 12 months. With the 2025 Genitourinary Cancers Symposium update on the phase 3 EV-302 trial [(NCT04223856), the median overall survival (OS) in that population] has gone up to 33.8 months [(95% CI, 26.1-39.3) with the use of enfortumab vedotin plus pembrolizumab].1 Patients are living longer, and the treatments have improved.

In 2025, there are 3 category 1 treatment options for patients with metastatic bladder cancer. One is enfortumab vedotin plus pembrolizumab based on the EV-302 study findings. When patients [in that trial were] treated [with this regimen, the overall response rate (ORR) was] 67.7% [95% CI, 63.1%-72.1%].2 That’s an effective regimen. In the past, we used to consider patients’ cisplatin or carboplatin ineligibility, but this regimen of enfortumab vedotin plus pembrolizumab can be used [regardless of patients’] cisplatin or carboplatin [eligibility]. That is my default [treatment option] right now, which I give to approximately 70% to 75% of my patients [with previously untreated advanced bladder cancer].

The second [treatment option] is cisplatin plus gemcitabine and nivolumab. This is also a standard-of-care treatment based on [data from] the phase 3 CheckMate 901 study [NCT03036098] for patients who are cisplatin eligible. Patients receive all 3 agents up-front. [In CheckMate 901], the [median] OS [with this regimen was] 21.7 months [95% CI, 18.6-26.4] vs 18.9 [months (95% CI, 14.7-22.4) with gemcitabine plus cisplatin alone, with an ORR of 57.6% [95% CI, 51.8%-63.2%] for the nivolumab arm.3 This is also a great treatment regimen.

The third [treatment option] is one we’re familiar with: the phase 3 JAVELIN Bladder 100 trial [NCT02603432] regimen of either cisplatin plus gemcitabine or carboplatin plus gemcitabine [for[4 to 6 cycles, and as long as patients have a complete response [CR] or a partial response, they continue with maintenance avelumab. That’s also an effective treatment regimen. We have a lot of options.

What patient characteristics or disease factors might lead you to choose one of the frontline chemotherapy-containing regimens instead of enfortumab vedotin plus pembrolizumab?

I [consider treatment options] besides enfortumab vedotin plus pembrolizumab for patients with severe diabetes mellitus or [elevated] hemoglobin or A1C [levels]. [I also avoid enfortumab vedotin in patients in whom] we are constantly checking glucose levels before treatment, [such as those] whose glucose levels are consistently over 300 mg/dL. [To use the] EV-302 [regimen], you have to make sure [patients’] sugar levels are controlled. [Norton Cancer Institute was] one of the leading enrollers for the phase 3 EV-301 study [(NCT03474107) of enfortumab vedotin in patients with previously treated advanced urothelial carcinoma], and we had to admit some patients [on that trial to the hospital] for diabetic ketoacidosis. It’s important to select the right patients for each treatment.

If I decide we can’t give a patient enfortumab vedotin plus pembrolizumab, what do I recommend? [That decision] boils down to cisplatin plus gemcitabine and nivolumab vs the JAVELIN-Bladder 100 regimen. Then the question is: Is the patient cisplatin ineligible? [Patients who are] cisplatin ineligible have a creatinine clearance above 60 mL/min and at least grade 1 sensory neural [effect]. You also [need to consider whether patients have] peripheral neuropathy. [If a patient has] peripheral neuropathy, I might not consider cisplatin, [nor would I] consider this agent in patients with] New York Heart Association Class III disease. If a patient is symptomatic with heart failure, you might not want to give them [cisplatin].

Then I start thinking about whether I want to use chemotherapy. In the JAVELIN Bladder 100 regimen, [you can use] gemcitabine plus either carboplatin or cisplatin followed by maintenance avelumab. Sometimes patients are a little older. They may not receive enfortumab vedotin or cisplatin because of the [associated] peripheral neuropathy. [In that case], I would give carboplatin plus gemcitabine and maintenance avelumab. The median OS [with the JAVELIN Bladder 100 regimen] has gone up to [23.8] months [95% CI, 19.9-28.8], so that is an effective treatment.4

Other features I consider are whether patients have elevated liver enzyme levels or cirrhosis. [In those patients], I shy away from enfortumab vedotin and lean more toward the CheckMate 901 regimen, and the JAVELIN Bladder 100 regimen. Additionally, I’ve noticed that a lot of patients are a little weaker, so sometimes if I were to give cisplatin/gemcitabine/nivolumab up front, that might [be associated with] more adverse effects [AEs] than [a regimen that is administered in 2 parts: chemotherapy first—whether gemcitabine plus cisplatin or carboplatin plus gemcitabine—followed by maintenance avelumab if [the patient achieves] a response. I’ve noticed in my practice that patients who receive chemotherapy in 2 parts tend to experience fewer AEs [than those who receive several agents up-front].

How does the presence of metastatic disease influence frontline bladder cancer treatment decisions?

One of the subgroup evaluations in CheckMate 901 [included patients with] lymph node–only metastatic urothelial cancers. Lymph node–only disease tends to be a better prognostic feature. The data [in this population] look strong for cisplatin plus gemcitabine and nivolumab, as well as for carboplatin or cisplatin plus gemcitabine and avelumab.

I look at [each patient’s] metastatic disease. Is it in the lung? Is it in the liver? Is it in the lymph nodes only? Enfortumab vedotin plus pembrolizumab [is also effective in] lymph node–only disease. However, enfortumab vedotin is such a strong medication post-platinum and post-immunotherapy. There is an opportunity for some oncologists to use enfortumab vedotin post-cisplatin. Every patient with metastatic bladder cancer should receive enfortumab vedotin if they qualify. However, you can also use it in second-line setting after cisplatin or carboplatin plus immunotherapy and gemcitabine.

In what patients might the avelumab-containing JAVELIN Bladder 100 regimen be the optimal treatment choice?

Whenever we [treat] patients approximately 70 or 80 years of age, we always [consider] chemotherapy, and alll the patients hear is the word ‘chemotherapy.’ I always share with patients that there are over 100 different cancers and [over] 100 different chemotherapies, and that each chemotherapy is associated with different AEs. I sometimes [consider chemotherapy in patients who are] older, those who have a weaker ECOG performance status—maybe ECOG 2 or borderline ECOG 1 disease—those with grade 2 or higher peripheral neuropathy, and those with a platelet count of 60,000/µl.

In the original [enrollment criteria] for EV-302, [patients needed to have] platelet counts above 100,000/µl and grade 2 or lower [peripheral neuropathy]. In patients approximately 75 to 80 years of age with a lot of comorbidities, I consider giving cisplatin—or more likely carboplatin, because they have a bit of a weaker ECOG performance status—in combination with gemcitabine. [After patients achieve a] response, [I continue treatment with] maintenance avelumab. For community oncologists, if you have a patient with known comorbidities—including liver disease or cisplatin ineligibility—that would be a good patient for carboplatin plus gemcitabine and maintenance avelumab.

What is the importance of using the most optimal treatment up front in each patient with bladder cancer?

In younger patients, you want to use the best treatment up front, and that would be enfortumab vedotin plus pembrolizumab, [which is associated with] the highest response rate and the highest median OS. Unfortunately, a lot of patients have comorbidities [that we need to consider]. It’s important to give the best treatment up front, but we also want to be mindful if patients have comorbidities.

For instance, if a patient has [difficult-to-manage], severe, grade 3 or 4 peripheral neuropathy because they have underlying diabetes mellitus, you might [achieve a good] response [with enfortumab vedotin], but at what price? This is where the art of medicine comes into play. [In most patients], you want to use the best treatment up-front. However, if patients have comorbidities, such as diabetes mellitus, underlying liver disease, or cisplatin ineligibility, you need to consider [other treatment options].

What are your recommendations for combining or sequencing treatments beyond the first-line setting for patients with bladder cancer?

Unfortunately, Gilead chose to withdraw [the United States indication for] sacituzumab govitecan-hziy [(Trodelvy) for the treatment of patients with metastatic urothelial cancer]. That was an effective treatment based on the phase 3 TROPiCS-04 trial [NCT04527991] data. I had patients [with good outcomes with that agent], and I still have patients receiving that medication. However, the company voluntarily withdrew that medication, removing another effective treatment. [That withdrawal was] controversial, because in TROPiCS-04, a lot of the patients had neutropenic fever in the first 3 months [of treatment with sacituzumab govitecan], and that hampered the OS data.

However, here in March 2025, because [the bladder cancer indication for] that medication has been removed, the question is: How do we sequence the various treatment options? If a patient is receiving enfortumab vedotin plus pembrolizumab and if their disease progresses, I have to start considering molecular markers. We have to check for FGFR3 alterations. The [FDA indication for erdafitinib (Balversa) for patients with bladder cancer harboring FGFR2 alterations has been] removed. [However, you may consider] erdafitinib [for patients with FGFR3 alterations]; that’s an effective treatment [that elicited a 35.3% (95% CI, 27.3%-43.9%) ORR in this population in the phase 3 THOR trial (NCT03390504)].5

You could also argue to use chemotherapy [in this setting], and then you would have to evaluate and use the Galsky criteria to see whether patients are cisplatin eligible. Most of those patients would be cisplatin ineligible because they progressed on enfortumab vedotin, and the peripheral neuropathy [associated with that antibody-drug conjugate] would put them into the platinum-ineligible [category]. [In that case], you would have to use carboplatin plus gemcitabine.

[You may also consider the] fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] pan-tumor [indication]. You would need to check for HER2 3+ [disease per] immunohistochemistry [IHC]. I have patients [with bladder cancer] who have received T-DXd based on the FDA pan-tumor approval.

However, if you have a patient who is progressing on carboplatin plus gemcitabine or cisplatin plus gemcitabine, the question is: Can you give them immunotherapy, such as avelumab? This is a data-free zone. I haven’t [used avelumab in this population], but Vadim S. Koshkin, MD, of the University of California San Francisco, generated interesting data on treatment rechallenge with immunotherapy, so this [strategy] might be emerging.

Then you start thinking about whether patients have a good ECOG performance status. [Patients in] the taxane arms of some bladder cancer studies, such as TROPiCS-04, [had good outcomes], so maybe you would consider a taxane there. For patients who have progressed on the CheckMate 901 regimen, you have to use enfortumab vedotin. [In patients with] FGFR3 alterations, randomized studies [have investigated] enfortumab vedotin plus erdafitinib, [and these 2 agents in sequence]. [In those patients], you could use the FGFR3-targeted erdafitinib before enfortumab vedotin. However, I would use enfortumab vedotin [in this setting], and if patients have an FGFR3 mutation, I would [subsequently] give erdafitinib.

Lastly, the question is: [What should we do after patients progress on] the JAVELIN Bladder 100 regimen? I would still use enfortumab vedotin after that, and then, if the patient has an FGFR3 alteration, I would give erdafitinib. Don’t forget about checking patients’ molecular statuses for HER2 IHC 3+, because [T-DXd has] a pan-tumor indication, and if you look for [and find HER2 expression], patients respond well to that treatment.

What data updates and paradigm shifts might be on the horizon in the perioperative bladder cancer treatment arena?

There are going to be a lot more studies coming in the perioperative setting. There were strong data from the phase 3 NIAGARA study [NCT03732677], which [Norton Cancer Institute] participated in, [showing the benefits of] chemotherapy and immunotherapy up-front, [followed by] cystectomy and continuous maintenance immunotherapy. I anticipate that [regimen will] be FDA approved in the next few months.

I also anticipate a lot of great data from the 2025 ESMO Congress from molecular studies, such as [those investigating] circulating tumor DNA [ctDNA]. A lot of patients [with bladder cancer achieve] pathologic CR [with their therapies]. Do we have another marker to see whether these patients can continue with observation? Some studies will mature, such as the phase 3 IMVIGOR011 trial [NCT04660344] evaluating [adjuvant atezolizumab (Tecentriq) in patients with ctDNA-positive, high-risk muscle-invasive bladder cancer (MIBC)], as well as the phase 2/3 MODERN study [NCT05987241] examining [the role of] ctDNA [in guiding immunotherapy use patients with resected bladder cancer].

[Another therapy that may be] FDA approved later in 2025 is the TAR-200 device. A lot of patients who are diagnosed with bladder cancer receive bacillus Calmette-Guérin [BCG] from a urologist. However, BCG stops working for some of these patients. The TAR-200 device looks like a long coffee straw, inside of which is gemcitabine. The straw is inserted inside the bladder, and it releases gemcitabine in a slow time-release fashion. At the 2024 ESMO Congress, the phase 2 SunRISe-1 study [NCT04640623] showed a durable ORR of 83.5% [(95% CI, 73.9%-90.7%) among patients with BCG-unresponsive non-MIBC who received TAR-200 monotherapy].6 We may have a lot of patients who qualify for this treatment post-BCG.

Why [are all these treatment developments] important for patient care? If a patient has localized bladder cancer, the last thing they want is to have their bladder removed. A lot of these therapies are moving into earlier lines of treatment, so patients can maintain their bladders.

References

1. Powles T, Van Der Heijden MS, Loriot Y, et al. EV-302: updated analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). J Clin Oncol. 2025;43(suppl 5). doi:10.1200/JCO.2025.43.5_suppl.664
2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117
3. van der Heijden MS, Sonpavde G, Powles T, et al. nivolumab plus gemcitabine-cisplatin in advanced urothelial carcinoma. N Engl J Med. 2023;389(19):1778-1789. doi:10.1056/NEJMoa2309863
4. Powles T, Park SH, Caserta C, et al. Avelumab first-line maintenance for advanced urothelial carcinoma: results from the JAVELIN Bladder 100 trial after ≥2 years of follow-up. J Clin Oncol. 2023;41(19):3486-3492. doi:10.1200/JCO.22.01792
5. FDA approves erdafitinib for locally advanced or metastatic urothelial carcinoma. FDA. January 19, 2024. Accessed April 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-erdafitinib-locally-advanced-or-metastatic-urothelial-carcinoma
6. van der Heijden MS, Simone G, Boegemann M, et al. LBA85 TAR-200 +/- cetrelimab (CET) and CET alone in patients (pts) with bacillus Calmette-Guérin-unresponsive (BCG UR) high-risk non-muscle-invasive bladder cancer (HR NMIBC): updated results from SunRISe-1 (SR-1). Ann Oncol. 2024;35(suppl 2):S1272-S1273. doi:10.1016/j.annonc.2024.08.2329