Recent Developments in Bladder Cancer

From a biomarker-driven strategy to delay or avoid cystectomy, to practice-changing perioperative immunotherapy, developments in bladder cancer frequently have made news over the past 12 months. The following summaries are among the noteworthy reports.

Bladder Preservation in Muscle-Invasive Bladder Cancer

With biomarker guidance after neoadjuvant chemotherapy, three-fourths of patients with muscle-invasive bladder cancer (MIBC) avoided cystectomy during 2 years of active surveillance, and almost half remained metastasis free with intact bladders at 40 months, in a phase II trial.

Results of this study could pave the way for more patients with MIBC to avoid cystectomy or radiation therapy for extended periods of time, offering improved quality of life.

“I think that the real key is we’re sort of pioneering an approach of allowing patients with muscle-invasive bladder cancer to preserve their bladders if they have an excellent response [to neoadjuvant therapy],” study author Daniel Geynisman, MD, of Fox Chase Cancer Center in Philadelphia, told MedPage Today. “This is where the field is trying to go, and this is one of the first trials to do so.”

Retrospective studies have shown that select patients who decline cystectomy for MIBC after a disease-free response to neoadjuvant chemotherapy have a disease-specific survival of about 90% and a bladder-preservation rate greater than 70%. A collaborative research effort has linked mutations in DNA-repair pathways to response to neoadjuvant chemotherapy — specifically ATM, RB1, FANCC, and ERCC2.

In their study, Geynisman and colleagues evaluated patients with newly diagnosed cT2-3N0M0 MIBC. Tumor specimens were analyzed for genomic mutations, and patients who had one or more mutations and achieved complete response (CR; cT0) after neoadjuvant chemotherapy were prospectively assigned to active surveillance.

Subsequently, 25 of 33 patients with one or more mutations opted for active surveillance. Eight of the 25 remained metastasis free during follow-up, and the remaining 17 had non-metastatic recurrence treated with intravesical therapy. The primary endpoint was metastasis-free survival at 2 years, which was achieved in 72.9% of patients, just missing the prespecified cutoff of 74% for statistical significance. At last follow-up, 12 of the 25 patients remained metastasis free with intact bladders.

Practice-Changing Results With Perioperative Durvalumab

Adding perioperative durvalumab (Imfinzi) to neoadjuvant chemotherapy significantly improved event-free survival (EFS) in MIBC, according to a phase III randomized trial.

Patients allocated to durvalumab had an estimated 24-month EFS rate of 67.8% versus 59.8% with neoadjuvant chemotherapy alone, a difference that translated into a 32% reduction in the hazard ratio (95% CI 0.56-0.82, P<0.001). The estimated 2-year overall survival (OS) rate was 82.2% versus 75.2% (HR 0.75, 95% CI 0.59-0.93, P=0.01).

“It’s working across various subgroups of patients, and the pathological complete response results, the significant overall survival benefit, and the shape of the curves underline the importance of both periods of therapy [adjuvant and neoadjuvant],” said Thomas Powles, MD, of Barts Cancer Institute in London, at the European Society for Medical Oncology annual congress.

Invited discussant Petros Grivas, MD, of Fred Hutch Cancer Center in Seattle, called the results practice changing.

“NIAGARA is the first trial that shows a clear EFS and OS benefit in the neoadjuvant and/or adjuvant setting, and in my opinion, that is an important differentiator,” he said.

Noting that the study could not distinguish the individual effects of neoadjuvant and adjuvant therapy, Grivas added, “Do we need either, or do we need both? In the future, as we go forward, we can think about teasing out the individual contribution.”

The NIAGARA trial involved 533 patients with cisplatin-eligible MIBC. They were randomized to neoadjuvant chemotherapy with or without durvalumab followed by cystectomy and adjuvant durvalumab. The trial had dual primary endpoints of EFS and pathologic complete response (pCR). The results showed that both favored the durvalumab arm, including pCR rates of 33.8% versus 25.8% (risk ratio 1.30, 95% CI 1.09-1.56, P=0.004).

A Win and a Setback for non-MIBC at the FDA

The FDA approved a first-in-class interleukin (IL)-15 agonist for bacillus Calmette-Guérin (BCG)-unresponsive non-MIBC (NMIBC).

Support for the approval of nogapendekin alfa inbakicept (Anktiva) came from the single-arm QUILT-3.032 trial. Patients received the IL-15 agonist and BCG maintenance. The primary endpoint was objective response.

The results showed that 62% of 77 evaluable patients achieved CRs. More than half (58%) of the responses were ongoing at 12 months and more than 40% were ongoing at 24 months. Some responses were ongoing at 47 months. The values exceeded previously established benchmarks for response.

“The long duration of complete response ranging over 47 months is a game changer for NMIBC patients and provides further clinical evidence of Anktiva’s effectiveness for patients who historically have faced high rates of recurrence and significantly diminished quality of life due to radical surgeries,” said Karim Chamie, MD, of the University of California Los Angeles, in a statement. “With this approval, Anktiva could represent a new standard of care for patients with NMIBC and has the potential to change the way we treat bladder cancer.”

Nogapendekin alfa is a novel IL-15 superagonist complex consisting of an IL-15 mutant (IL-15N72D) fused with an IL-15 receptor alpha, which binds with high affinity to IL-15 receptors on natural killer, CD4, and CD8 T cells. The drug enhances natural killer cell recruitment and stimulates T-cell activity and innate immune memory response to enhance tumor cell killing.

The news was less favorable for the investigational agent UGN-102 as a nonsurgical alternative to transurethral resection of bladder (TURBT) for recurrent low-grade NMIBC. By a 5-4 vote, the Oncologic Drugs Advisory Committee (ODAC) decided that the therapy’s risks outweigh the potential benefits.

Results of the ENVISION trial showed a 3-month CR rate of 77.6% among 223 patients, and 79% of the responses lasted a year or longer. However, in a report prepared for ODAC, FDA staff stated that the single-arm trial did not clearly show that the observed responses resulted from the treatment or reflected the natural history of the disease. Staff members also noted a higher incidence of genitourinary symptoms with UGN-102 as compared with TURBT.

UGN-102 showed a higher CR rate versus TURBT in the randomized ATLAS trial. However, the study ended prematurely, and FDA staff asserted that the results should be considered exploratory only.

“Without a full randomized trial … it’s very hard to determine the true benefit of this,” said ODAC Acting Chair Daniel Spratt, MD, of Case Western Reserve University in Cleveland. “While I understand from the experts in this field that a 3-month CR rate is kind of a standard in this field … the follow-up to me is far too short in this indolent disease process to know how this will impact subsequent salvage therapies.”

Sponsor Pulls Accelerated Approval

The accelerated approval of sacituzumab govitecan (Trodelvy) for previously treated advanced/metastatic urothelial cancer will be voluntarily withdrawn, according to Gilead Sciences.

Contingently approved for the indication in 2021, conversion to full approval required a positive confirmatory trial. The accelerated approval was based on results of the phase II TROPHY U-01 trial, which showed an objective response rate of 27% and median duration of response of 5.9 months.

Subsequently, the phase III TROPiCS-04 trial failed to meet the primary endpoint of improved OS with the TROP-2 inhibitor versus physician’s choice of single-agent chemotherapy. The drug achieved a numerical improvement in OS, but the difference did not achieve statistical significance, as more deaths related to adverse events occurred with sacituzumab govitecan.

The withdrawal does not affect the status of the monoclonal antibody’s approved indication in previously treated advanced/metastatic breast cancer.

Personalized Radiotherapy Promising but Complicated

A personalized strategy of radiotherapy (RT) for bladder cancer led to a low rate of severe late toxicity and an OS that compared favorably with cystectomy.

Only one of 114 patients developed grade ≥3 adverse events with two different fractional protocols of dose-escalated adaptive RT (DART). Two-year OS was 80% with DART versus 77% with standard whole-bladder RT or standard-dose adaptive RT. Subsequently, 13 of 345 patients treated with any of the three RT strategies underwent radical cystectomy, reported Robert Huddart, MBBS, PhD, of the Royal Marsden Hospital in London, and co-authors.

The DART protocol allowed for adjustment of RT volume and dose on the basis of bladder size and position at each clinic appointment.

“An image-guided adaptive strategy enabled radiotherapy dose escalation to over 86% of patients’ bladder tumors without significant increase in toxicity,” the authors concluded. “Utilization of multiple adaptive plans suggests an ongoing need for adaptive therapy to optimize treatment delivery. Dose-escalated therapy achieves promising tumor control and survival rates similar to that achieved with cystectomy, with low rates of salvage cystectomy, and should be studied in future trials.”

DART offers a potential strategy to address the common problem of local recurrence in bladder cancer, according to Krishnan Patel, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Maryland.

“Since they sort of knew the tumor was coming right back to where they initially saw it, these investigators wanted to see if pushing the radiation doses and really aggressively killing the cancer would improve the efficacy,” Patel, an expert for the American Society for Radiation Oncology, told MedPage Today. “Underlying this is the logic that more radiation dose kills more cells and therefore improves tumor control. That’s kind of the rationale that underlies the whole field of radiation therapy.”

DART strategies are complicated by anatomy: The intestines lies on top of the bladder and the rectum behind it. Both are particularly sensitive to the effects of radiation, as compared with the bladder, Patel continued. Additionally, bladder volume changes throughout the day, another complicating factor. The authors tried to address the problem by standardizing bladder volume. Before treatment, patients emptied the bladder and then consumed a specific amount of liquid to maintain the same volume at each treatment session.

“Suffice to say, no matter how much we try to do these things to standardize bladder size, it’s not standardized,” said Patel. “Even if you tell a patient to do the exact same thing on a particular day, the bladder will still have different volumes, and therefore the interface between the bladder and intestines will be different on different days.”