Durvalumab/Radiotherapy May Fill Unmet Medical Need in Bladder Cancer Subset

Yousef Zakharia, MD

Treatment with radiation and the immune checkpoint inhibitor durvalumab (Imfinzi) appeared to be safe, tolerable, and showed a disease control rate (DCR) of 92% in patients with locally advanced and unresectable bladder cancer who are cisplatin-ineligible/unfit for surgery, according to findings from the DUART study (NCT02891161).

DUART investigated the combination in 26 patients, for which durvalumab was dosed at 1500 mg and administered with definitive radiotherapy at 64.8 Gy across 36 fractions. The investigators hypothesized that the addition of durvalumab would increase the progression-free survival (PFS) by 25%, and the DCR was predicted to be 75%.

The probable results at 1 year were close to the original predictions in the study, according to findings presented during the 2021 Genitourinary Cancers Symposium. Full results from the study are upcoming.

In an interview with Targeted Oncology™, study co-investigator Yousef Zakharia, MD, clinical associate professor, director, Phase 1 Program, and co-leader, Genitourinary Oncology Program, Internal Medicine a University of Iowa, explained the background and results of the DUART study.

TARGETED ONCOLOGY™: What are the current treatment options available for patients with bladder cancer who are cisplatin ineligible or unfit for surgery?

Zakharia: For patients who are cisplatin ineligible, but they are fit for surgery, typically, we take them directly to surgery. But for patients who are not fit for both, neither for cisplatin nor for surgery, radiation therapy plus chemotherapy is the treatment of choice.

What was the rationale for using durvalumab and radiation for the treatment of these patients?

In the realm of anti-PD-L1 inhibitors, it's already FDA approved for metastatic bladder cancer after progression on chemotherapy. We know nowadays that immunotherapy plus radiation therapy work hand-in-hand. That was the rationale of combining immunotherapy development with radiation therapy in this patient population who are typically frail and not eligible for chemotherapy. Having immunotherapy on board with radiation might be more tolerable.

Can you explain the design of this study?

This clinical trial was for patients with muscle invasive bladder cancer, or stage TII to IV disease for disease with positive pelvic lymph adenopathy, but not distant metastatic disease. Patients would get concurrent development plus radiation therapy to the pelvis, followed by maintenance durvalumab monthly for a total of 1 year of treatment with a primary end point of progression-free survival rate at the first year. The other primary end point was disease control rate post both treatments of the concurrent development of radiation and the adjuvant development. The secondary endpoint was other efficacy measures like overall survival and overall response rate. And we are doing some correlative end points or correlative studies related to this clinical trial.

What were the efficacy findings of this study?

We enrolled a total of 26 patients on this clinical trial and of those, we had efficacy data on 24 patients. We previously discussed the safety data at another meeting, and the combination was deemed safe without major dose-limiting toxicity that we encountered with this combination. Of the 24 patients that we enrolled on that clinical trial, we had a disease control rate of 72% at the end of 1 year, with a progression-free survival rate of about 70% and an overall survival probability at the first year of 83%.

Were there any toxicities that oncologists should be aware of with this combination?

The combination was well-tolerated. The adverse events profile was in line with what you would expect with the radiation therapy or with immunotherapy including, diarrhea, some fatigue, some cystitis from the radiation. There was nothing major outside what you would expect with this combination with either of these drugs.

Do you have any final comments about your study?

I think this data despite the fact it's still a small number of patients, is exciting. Most importantly, the treatment combination seems to be tolerable. Obviously, we look forward to following these patients longer, and we look forward to replicating this data in efficacy data in the larger status.

What are the next steps with this research?

There is now an ongoing clinical trial through ECOG It's EA8185 with the chair, Dr. Monika Joshi from Penn Medicine. This trial is using chemoradiation with or without durvalumab. This trial is currently recruiting.

What are some unanswered questions you have with treating this patient population that you hope ongoing research will address?

For this patient population, still, it can be challenging because we do not have too many treatment options available for them. And many of them will have disease recurrence down the road. So that's why we are excited about these preliminary results that we are seeing in this pilot study. We hope or look forward to replicating these results in the large phase 3 trials down the road.

For example, for patients who are cisplatin ineligible, and they are fit for clinical trials, there are ongoing neoadjuvant treatment studies using immunotherapy and in that setting, followed by surgery. That is the current option for patients who are ineligible for cisplatin but eligible for surgery.

_Reference:

_{Joshi M, Kaag M, Tuanquin L, et al. Phase II clinical study of concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: Results for primary analyses and survival. BTCRC-GU15-023. J Clin Oncol. 2021;39(suppl6; 398). doi: 10.1200/JCO.2021.39.6_suppl.398}