BCG Failure in Bladder Cancer Is Now Rare: Is Adding Immunotherapy Worth It?
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Adding Immunotherapy to BCG: Is It as Promising as It Looks?
Why does it matter, and how did we get here?
Non-muscle-invasive bladder cancer (NMIBC), the early form in which cancer has not reached the bladder's muscle layer, accounts for approximately 70% of bladder cancers. These patients generally receive treatment after transurethral resection of bladder tumor (TURBT) . However, the main challenges are their high risk of recurrence and, in some cases, the potential for progression to an invasive stage .
In the late 1970s, Bacillus Calmette–Guérin (BCG)was found to activate the immune system and eliminate cancer cells when administered into the bladder. The first clinical trials, led by Alvaro Morales in 1976, produced a dramatic difference compared with the standard treatments of the time. BCG thus became cancer immunotherapy's first successful example in history.
For nearly half a century, BCG remained the "gold standard" for NMIBC. Over time, however, two main problems emerged: (1) Disease recurred in some patients despite treatment. (2) Global shortages in BCG production made this treatment difficult to access.
During this period, researchers turned toward new agents that activate the immune system more selectively: immune checkpoint inhibitors. PD-1 and PD-L1 blockade began producing impressive responses, particularly in advanced bladder cancer. Following this wave, in 2020, the FDA approved pembrolizumabfor patients with BCG-resistant NMIBC —the first to be administered systemically rather than into the bladder .
However, that approval applied to a very specific group: patients whose disease recurred despite BCG but had not spread systemically. This success prompted a new question: "Could adding immunotherapy to BCG from the start further reduce recurrence rates?"
Large trials presented at ESMO 2025, including POTOMAC, ALBAN and CREST , were phase 3 studies seeking to answer exactly this question. Their results, however, showed that this approach does not work for every patient and may carry a greater cost than expected.
Three Major Studies: POTOMAC, ALBAN, and CREST
Although BCG's historical success is undisputed, not every patient achieves a complete response. In recent years, researchers have therefore asked: "Can adding systemic immunotherapy to BCG reduce recurrence?" Three large phase 3 trials presented at the ESMO 2025 Congress sought the answer:
- POTOMAC: BCG + durvalumab (Imfinzi)
- ALBAN: BCG + atezolizumab (Tecentriq)
- CREST: BCG + sasanlimab (an experimental PD-1 inhibitor)
All three trials enrolled BCG-naive patients with high-risk NMIBC . All patients had previously undergone transurethral resection (TURBT) , and treatment used BCG induction + maintenance protocols. Immunotherapy was given alongside BCG or alone.
POTOMAC: 2-year disease-free survival (DFS) rate 86.5% vs 81.6% — an absolute difference of only 4.9%.
CREST: 3-year event-free survival (EFS) 82.1% vs 74.8% — a difference of 7.3%.
ALBAN: Adding atezolizumab provided no clinical benefit.
The results can be summarized as follows: Adding immunotherapy may reduce recurrence risk in a small group of patients, but the overall benefit is limited. Although these differences are statistically significant, their clinical meaning—the effect on survival or the chance of preserving the bladder—remains uncertain.
⚠️ Small Benefit Versus Major Side Effects
Immunotherapy aims to destroy cancer cells by stimulating the immune system. During this process, however, the immune system can sometimes become "uncontrolled" and damage healthy tissues. The most important limitation of PD-1 and PD-L1 inhibitors is therefore immune-related toxicities.
- CREST: Severe (grade ≥3) adverse events: 29.1% (sasanlimab) vs 6.3% (BCG alone)
- POTOMAC: 21% (durvalumab) vs 4% (BCG)
- ALBAN: Similar toxicity rates
In other words, toxicity rates increased 4- to 5-fold. These findings show that a small reduction in recurrence may come at a high cost. Immune-mediated hepatitis, colitis, or endocrine side effects can cause permanent damage in some patients.
🩺 What Should the "Real Benefit" Be?
None of these studies adequately assessed “cystectomy-free survival” —that is, the rate of bladder preservation . Yet for these patients, the main goal is preserving the bladder rather than extending survival.
We are discussing perhaps preventing a few additional TURBT procedures rather than saving lives.
Indeed, these trials did not produce a significant difference in survival or bladder preservation. The "real benefit" may therefore be only fewer operations among patients with recurrence.
BCG’s "Comeback"
New data show that the often-repeated historical claim that "40% of BCG treatment fails within 2 years" is no longer valid. With modern surgical techniques, appropriate BCG dosing, and maintenance treatment, more than 75% of patients can now remain disease-free at 2 years.
This brings an important shift in understanding: BCG is actually much more effective than we thought. Lower failure rates today remind us that BCG remains a powerful immune activator.
Our patients are now doing much better; immunotherapy may complement BCG in the right patient rather than replace it.
Looking Ahead
Although BCG + immunotherapy began as a promising approach, it is not currently a solution for everyone. Current data suggest that the proportion of patients who truly benefit may be around 5% .
The next stepis to identify this 5% accurately. Which patients have a tumor microenvironment sensitive to immunotherapy, and which do not? The answer will shape future biomarker-guided bladder cancer treatments .
Perhaps the next stage will be combinations of BCG + checkpoint inhibition selected using the right biomarker rather than simply "BCG + checkpoint."
DROZDOGAN Academy Commentary
These trials remind us of a familiar reality in oncology: not every biological promise can immediately be translated into clinical practice. A treatment as old as BCG remains relevant because it can stimulate the immune system at the right level on the bladder surface. Systemic immunotherapy is an exceptionally powerful weapon; it benefits some patients while exposing others to unnecessary toxicity.
Bladder cancer is one of the most complex settings in immune biology. The future therefore lies in "more selective treatment" rather than more treatment. Checkpoint inhibitors are not leaving the field; they are waiting for the right patient selection .
Sources: ESMO 2025; POTOMAC (AstraZeneca), ALBAN (Roche), and CREST (Pfizer) phase 3 trials; McGregor B, Roupret M. ESMO 2025 Presentations and Press Sessions.
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