FDA approves durvalumab for perioperative immunotherapy for patients with muscle-invasive bladder cancer

The US Food and Drug Administration has approved the first perioperative immunotherapy (durvalumab) for patients with muscle-invasive bladder cancer. The approval is for a regimen of neoadjuvant durvalumab combined with gemcitabine or cisplatin (every 3 weeks for four cycles) before radical cystectomy followed by single-agent adjuvant durvalumab (every 4 weeks for eight cycles).^{1, 2}

Before this approval, the standard of care for patients with muscle-invasive bladder cancer was neoadjuvant chemotherapy followed by radical cystectomy for cisplatin-eligible patients.

The approval is based on the results of the phase 3 NIAGARA trial, an open-label trial that included 1063 patients who were candidates for radical cystectomy and had not received prior systemic therapy for bladder cancer. The patients were randomized to neoadjuvant durvalumab with chemotherapy followed by adjuvant durvalumab after surgery (n = 533) or neoadjuvant chemotherapy followed by surgery alone (n = 530).³

In a prespecified planned interim analysis, significant improvement was seen in both the main outcome, event-free survival (EFS), and the secondary outcome, overall survival (OS), in the durvalumab-treated group. At 24 months, the estimated EFS rate was significantly greater in the durvalumab-treated group (67.8%) than the chemotherapy/surgery–alone group (59.8%); this represented a 32% reduction in the risk of disease progression, recurrence, not undergoing radical cystectomy, or death from any cause (hazard ratio [HR], 0.68; 95% CI, 0.56–0.82; p < .001). The median EFS was 46.1 months in the chemotherapy/surgery–alone group and was not reached in the durvalumab-treated group.^1-3

OS at 24 months also was significantly greater in the durvalumab-treated group versus the chemotherapy/surgery–alone group (82.2% vs. 75.2%; HR, 0.75; 95% CI, 0.59–0.93; p = .01). Neither arm had reached median survival at the time of the analysis.^1-3

No new safety signals were seen; adverse reactions were consistent with those previously seen with durvalumab with platinum-based chemotherapy. Grade 3 or 4 treatment-related adverse events occurred in the durvalumab-treated group (40.6%) and the chemotherapy/surgery–alone group (40.9%), and treatment-related adverse events leading to death occurred at the same rate in the two groups (0.6%).^{2, 3}

The majority of patients in both groups were able to undergo radical cystectomy (88% in the durvalumab-treated group and 83.2% in the chemotherapy/surgery–alone group).³

The recommended dose of durvalumab is based on a body weight of ≥30 kg: 1500 mg every 3 weeks with chemotherapy (neoadjuvant treatment) and 1500 mg as a single-agent therapy (adjuvant treatment) every 4 weeks. The recommended durvalumab dose for patients weighing <30 kg is 20 mg/kg with chemotherapy (neoadjuvant treatment) every 3 weeks and 20 mg/kg as a single-agent therapy (adjuvant treatment) every 4 weeks. Treatment should continue until disease progression (precluding definitive surgery, recurrence, or unacceptable toxicity) or for a maximum of eight cycles after surgery.¹

Experts weigh in

Pointing out that approximately one half of patients with muscle-invasive bladder cancer have a recurrence despite standard treatment with cisplatin-based chemotherapy followed by radical cystectomy, Timothy Lyon, MD, a urologic medical oncologist and surgeon at the Mayo Clinic Comprehensive Cancer Center in Jacksonville, Florida, calls the approval of the durvalumab-based perioperative treatment approach “an exciting new treatment advance” in this setting and says that he and his colleagues plan on offering it to their patients.

He notes that the addition of durvalumab to perioperative treatment had no impact on the patient’s ability to undergo subsequent surgery, and there was no difference in complication rates after cystectomy seen with the durvalumab regimen compared to the standard of care.

However, he cautions that choosing the appropriate patient for the durvalumab-based perioperative treatment is critical, as the regimen may lead to overtreatment for some patients. He says that an alternative strategy would be to use only chemotherapy in the perioperative setting and immunotherapy in the postoperative setting in patients with an advanced pathological stage after surgery. “This would allow immunotherapy to be given to the patients that need it most while helping others with a low risk of relapse to avoid its potential toxicity,” he says.

“Ultimately, choice of regimen will come down to a process of shared decision-making based on each patient’s individual treatment goals and the risks they are willing to accept to achieve their desired outcomes,” he says. “We’re hopeful that future work will help clarify whether biomarkers such as circulating tumor DNA can help refine patient selection.”

Daniel M. Geynisman, MD, chief of the Division of Genitourinary Medical Oncology at the Fox Chase Cancer Center in Philadelphia, Pennsylvania, calls the durvalumab-based perioperative regimen a strong new option for all patients with muscle-invasive bladder cancer. “It will hopefully increase the proportion of patients receiving immunotherapy and importantly cisplatin-based chemotherapy, which has been difficult to achieve historically,” he says, adding that it will also hopefully increase the number of patients cured.

He notes that not all patients are eligible for cisplatin treatment and emphasizes that substituting carboplatin for cisplatin was not permitted in the trial; therefore, the results cannot be extrapolated to the setting in which carboplatin is used. “Cisplatin-ineligible patients will need different treatment regimens,” he says.

For Dr Geynisman, a key point of the study is emphasizing that neoadjuvant therapy in bladder cancer is a key part of the multidisciplinary care of these patients and should be discussed with them. He says that he intends to discuss the durvalumab-based regimen with his cisplatin-eligible patients but also the alternative of using neoadjuvant cisplatin-based chemotherapy followed by adjuvant immunotherapy in select patients. “One downside of the new regimen is that it treats all patients with immunotherapy, many of whom either do not need it or do not benefit from it,” he says. “In other words, there is going to be overtreatment as a result.”

Hamed Ahmadi, MD, an assistant professor in the Department of Urology at the University of Minnesota Medical School in Minneapolis, describes the finding as a “big step forward” that provides another tool in the toolbox for treating muscle-invasive bladder cancer. However, he also voices some concern that some patients may be overtreated, as he notes that approximately 65% of patients either have a complete response or do not have muscle-invasive disease after the initial systemic treatment.

“Not everyone will need immunotherapy after surgery, so I’d like to see better ways to figure out who actually benefits from it before making it standard for everyone.”