BCG Monotherapy Remains the Preferred First Move in BCG-Naive High-Risk NMIBC

Bacillus Calmette-Guérin (BCG) monotherapy should remain the preferred first-line treatment for patients with BCG-naive, high-risk non–muscle-invasive bladder cancer (NMIBC) because contemporary outcomes with BCG have improved and add-on strategies offer limited benefit in unselected patients, according to a presentation from Vignesh T. Packiam, MD, that was delivered at the 2026 LUGPA Annual Meeting.¹

Packiam noted that BCG has historically been described as effective in 60% to 65% of patients, but recent phase 3 trials show higher rates of disease control. The 2-year recurrence-free survival (RFS) rate was 85% in the standard-frequency BCG arm of the phase 3 NIMBUS trial (EudraCT 2010-019181-91; n = 175) and approximately 80% in the BCG induction and maintenance arm of the phase 3 CREST trial (NCT04165317; n = 351), meaning that only 15% to 20% of patients experienced recurrence.

He attributed much of that improvement to better transurethral resection of bladder tumor (TURBT) rather than to changes in BCG itself, citing greater use of bipolar resection, routine re-resection of high-grade T1 disease, blue light cystoscopy to detect and resect carcinoma in situ (CIS), and more consistent imaging at diagnosis.

"BCG monotherapy still works very, very well. All of our contemporary studies show that efficacy has improved substantially," said Packiam, who is an associate professor of urologic oncology at Rutgers Cancer Institute of New Jersey and Rutgers Robert Wood Johnson Medical School in New Brunswick. "I think [BCG] deserves to continue to be level 1 treatment."

How does the 2026 AUA guideline define high-risk NMIBC?

Packiam explained that the prior American Urological Association (AUA) risk stratification placed some favorable high-grade papillary tumors in the intermediate-risk group alongside complex low-grade disease, although studies have shown that high-grade disease behaves similarly regardless of size or focality. The 2026 amendment to the AUA/Society of Urologic Oncology guideline reflects what he described as common practice by classifying any high-grade disease, including CIS, T1, and high-grade Ta tumors, as high risk.² The AUA, European Association of Urology, and National Comprehensive Cancer Network guidelines all recommend BCG as the first-line treatment for high-risk disease.¹

What did CREST and POTOMAC show for checkpoint inhibitors plus BCG in BCG-naive NMIBC?

In CREST, 17.3% of patients treated with sasanlimab plus BCG induction and maintenance (n = 352) experienced an event-free survival (EFS) event vs 25.4% of those given BCG induction and maintenance alone (HR, 0.68; 95% CI, 0.49-0.94; 1-sided P = .0095). The phase 3 POTOMAC trial (NCT03528694) of durvalumab (Imfinzi) plus BCG, which supported the FDA approval of that combination in May 2026, was also positive.³ Packiam said that across the 2 trials, adding a checkpoint inhibitor improved RFS by approximately 5% at 2 years in all comers, with no difference in progression, cancer-specific survival, or overall survival, and with 15% to 20% more grade 3 or higher adverse effects.¹ If the goal is to limit toxicity, he said, clinicians may think twice about adding checkpoint inhibition for all patients.

Is gemcitabine/docetaxel an alternative to BCG in BCG-naive high-risk NMIBC?

Gemcitabine/docetaxel, initially used after BCG recurrence, moved into the first-line setting at some centers during BCG shortages. In a retrospective cohort study from the University of Iowa that included patients with AUA high-risk, treatment-naive NMIBC treated with BCG (n = 174) or sequential intravesical gemcitabine and docetaxel (n = 138), the 2-year high-grade RFS rate was 81% with gemcitabine/docetaxel vs 69% with BCG (HR, 0.57; 95% CI, 0.33-0.97).⁴ Packiam, the study's senior author, said that with the caveat of its retrospective design, the data suggest the regimen performs similarly to BCG.¹ A prospective series of patients with AUA high-risk NMIBC (n = 25) reported a 3-month complete response rate of 100% and a 1-year complete response rate of 92% with gemcitabine/docetaxel, which he described as essentially identical to rates in modern BCG studies.

The phase 3 ECOG-ACRIN EA8212 BRIDGE trial (NCT05538663), which randomly assigned patients with BCG-naive high-grade NMIBC to gemcitabine/docetaxel or BCG with EFS as the primary end point, has completed enrollment. "I think we're going to learn the true answer of this in the next few years," Packiam said.

He was less favorable toward BCG plus mitomycin. In the phase 3 ANZUP 1301 trial (NCT02948543), the 2-year high-grade RFS rate was 82% with BCG plus mitomycin (n = 249) vs 79% with BCG alone (n = 252). Packiam characterized the study as essentially negative, noting that patients received additional active treatment and exposure to mitomycin without a reduction in recurrence.

How should clinicians select first-line therapy for BCG-naive high-risk NMIBC?

Packiam outlined a treatment-naive philosophy built on 5 goals: a strong response, limited toxicity, preserved BCG supply, preserved eligibility for salvage therapy, and avoidance of combination therapy without added benefit. Under that framework, BCG monotherapy delivers a strong response; gemcitabine/docetaxel is the key option when BCG supply is limited or unavailable, although he acknowledged it can be difficult to deliver in many practices; and patients should receive some BCG when possible, because the newly FDA-approved salvage therapies are indicated for BCG-unresponsive disease.

"You don't want to give additional treatment if it's not providing additional benefit for the patient," he said.

Beyond clinicopathologic features such as age and tumor stage, Packiam described an artificial intelligence–augmented digital histopathology biomarker that analyzes more than 600 microscopic features on a hematoxylin and eosin–stained slide. In a retrospective study, the biomarker was present in approximately 30% of patients. Among those with biomarker-present tumors, the 2-year high-grade RFS rate was 90% with gemcitabine/docetaxel (n = 33) vs 56% with BCG (n = 44); among those with biomarker-absent tumors, there was no significant difference between gemcitabine/docetaxel (n = 61) and BCG (n = 115). A prospective validation study is underway.

What role does TURBT quality play in outcomes for BCG-naive high-risk NMIBC?

Packiam called TURBT one of the most important and most difficult procedures in this setting. He cited the phase 3 JCOG1019 trial (UMIN000006390), in which patients with high-grade T1 disease and no residual tumor on re-resection were randomly assigned to active surveillance (n = 130) or 8 weekly BCG induction instillations (n = 133). Although active surveillance was associated with approximately 20% more recurrences, there was no difference in progression or survival. He described the findings as provocative but not practice-changing, adding that they suggest a complete resection drives many of the outcomes attributed to intravesical therapy.

He recommended repeat TURBT for patients with T1 disease and extensive high-grade Ta disease, noting that re-resection is therapeutic even when negative. Packiam uses blue light cystoscopy in almost all of his TURBTs, citing a meta-analysis of 12 randomized trials including 2288 patients in which enhanced cystoscopy improved detection of Ta/T1 tumors by approximately 15% and CIS by more than 40%, and decreased recurrence by approximately 10% to 15%. In surveillance, approximately 19% of patients who had received 3 or more prior intravesical therapies had disease detected only with blue light cystoscopy, and he said he incorporates it for patients who have received 2 or 3 prior intravesical therapies.

References

1. Packiam VT. First move matters: optimizing the BCG-naïve patient. Presented at: 2026 LUGPA Annual Meeting; November 5-7, 2026; Chicago, IL.
2. Kret R. AUA releases guideline amendment for NMIBC. OncLive. Published October 3, 2026. Accessed November 5, 2026. https://www.onclive.com/view/aua-releases-guideline-amendment-for-nmibc
3. OncLive Staff. Durvalumab plus BCG improves DFS in papillary-only, BCG-naive high-risk NMIBC in POTOMAC. OncLive. Published October 24, 2026. Accessed November 5, 2026. https://www.onclive.com/view/durvalumab-plus-bcg-improves-dfs-in-papillary-only-bcg-naive-high-risk-nmibc-in-potomac
4. McElree IM, Steinberg RL, Mott SL, O'Donnell MA, Packiam VT. Comparison of sequential intravesical gemcitabine and docetaxel vs bacillus Calmette-Guérin for the treatment of patients with high-risk non-muscle-invasive bladder cancer. JAMA Netw Open. 2023;6(2):e230849. doi:10.1001/jamanetworkopen.2023.0849