Bladder-Sparing Therapies Show Promise for Nonmuscle-Invasive Bladder Cancer

By Will Boggs MD

April 09, 2020

NEW YORK (Reuters Health) - Several bladder-sparing treatments appear to improve response rates and survival in patients with non-muscle-invasive bladder cancer (NMIBC) who experience recurrence despite bacillus Calmette-Guerin (BCG) therapy, according to a systematic review and meta-analysis.

"A lot of progress has been made developing bladder-preserving therapies for BCG-unresponsive high-grade bladder cancer," Dr. Ashish M. Kamat of the University of Texas MD Anderson Cancer Center, in Houston, told Reuters Health by email. "For clinical development programs, consistent endpoint reporting and standardized patient-population definitions remain critical to allow for a valid cross-trial comparison of study findings."

Transurethral resection of the bladder tumor, followed by adjuvant therapy with intravesical BCG, is the standard treatment for high-risk NMIBC. There is no standard of care for patients whose cancer recurs despite BCG therapy. Radical cystectomy is commonly recommended, but many patients decline or are ineligible for such surgery.

Dr. Kamat and colleagues assessed the efficacy and safety evidence of current and emerging treatments for patients with NMIBC that recurs following BCG treatment in their analysis of 30 studies (19 full-text articles and 11 abstracts).

"Both the FDA and the International Bladder Cancer Group (IBCG) have put together guidance documents on clinical-trial design for non-muscle-invasive bladder cancer and BCG-unresponsive high-grade patients, in particular," Dr. Kamat explained.

"We found considerable variation across those studies published before 2018 when the FDA (Food and Drug Administration) guidance was issued. Therefore, having these studies reviewed together really gives us the opportunity for a deep understanding of the historical data, hence the realization of a potential lack of comparability of such results, and for us to keep in mind what we should look for going forward."

Reported efficacy outcomes included complete responses (CR, 23 studies), relapse-free survival (RFS, nine studies), disease-free survival (DFS, eight studies) and overall survival (OS, five studies), the team reports in European Urology Oncology.

In 10 studies of patients with one or more prior BCG courses, the pooled estimated three-month CR/RFS/DFS was 60%, with substantial heterogeneity and with different outcomes by the percentage of patients included with carcinoma in situ (CIS).

In studies enrolling 50% or more patients with CIS, three-month CR/RFS/DFS ranged from 29% for mitomycin C (MMC) to 70% for BCG plus interferon, with an overall pooled estimate of 49%. In studies with fewer than half of patients with CIS, on the other hand, the pooled estimate was 85%.

The 12-month CR/RFS/DFS rate for the 50% or more CIS subgroup ranged from 10% for valrubicin to 48% for MMC, with an overall pooled estimate of 23%, whereas the rate for the under-50% CIS subgroup ranged from 47% for BCG plus interferon to 62% for MMC, with an overall pooled estimate of 48%.

In 6 studies of patients with two or more prior BCG courses, the pooled estimated three-month CR/RFS/DFS rate was 46% and the pooled estimated 12-month CR/RFS/DFS rate was 24%, both with moderate heterogeneity.

The three-month CR/RFS/DFS rate in this subgroup was highest for paclitaxel-hyaluronic acid (73%) and nadofaragene firadenovec (68%), whereas the 12-month CR/RFS/DFS rate was highest for nadofaragene (37%) and lowest for paclitaxel-hyaluronic acid (9%).

Treatment-related adverse event rates ranged from 9.1% for paclitaxel-hyaluronic acid to 85.0% for nadofaragene.

Other agents showing promise in observational studies included doxorubicin plus MMC, gemcitabine plus MMC, and hexaminolevulinate-based photodynamic therapy.

"The treatments included in our review are both conventional chemotherapies and several emerging treatments," Dr. Kamat said. "The treatment options have been rather limited historically until nadofaragene firadenovec, pembrolizumab, and vicinium, which are among the emerging treatments."

"These treatments could offer more options for this historically difficult-to-treat patient population who wants to have bladder-preserving therapies," he said. "It is really a good thing for these patients having different treatment options."

Dr. Kamat added, "It is important to consider the patient characteristics when reviewing clinical-trial evidence and making treatment recommendation. Results from our meta-analysis support previous findings that a higher number of previous BCG courses, BCG-refractory/unresponsive status, CIS, and high-grade tumors are associated with lower treatment response. This finding is particularly important when interpreting results from studies that may have included less severe patients, such as some observational studies on intravesical chemotherapy agents."

Dr. Yair Lotan of UT Southwestern Medical Center at Dallas, in Texas, an expert in bladder cancer who was not involved in the study, told Reuters Health by email, "The current best chance of cure for these patients is bladder removal (cystectomy), but this is a morbid operation with lifelong quality of life implications. Patients would prefer to avoid this surgery, but the risk is disease progression and death from bladder cancer."

"The issue with all current agents is that they have early reasonable (but not great) responses ranging from 40-50%, but by 1 year most have less than a 30% overall response," he said. "This means that we still need to find solutions that will provide long-term benefit."

"Pembrolizumab was recently approved by the FDA for these patients," Dr. Lotan said. "There is approximately 40% response at 3 months and 60% of these patients maintain a response by 1 year. Nadofaragene will likely get approval later this year, with around a 50% response at 3 months of which 50% maintain a response at 1 year. Sequential intravesical chemotherapy with gemcitabine and docetaxel is also available, but the data for such combinations is not as robust."

"It is unclear how well these agents will work in sequence or if combinations will be more effective," he said.

FerGene Inc., a subsidiary of Ferring Pharmaceuticals created to commercialize nadofaragene firadenovec, provided funding for the review. Dr. Kamat and several coauthors report financial ties to Ferring and other companies that produce some of the therapies in the review. Dr. Lotan is a consultant for Merck and FerGene.

SOURCE: European Urology Oncology, online March 19, 2020.