Updated data ‘further supports’ adjuvant chemotherapy for upper tract urothelial cancer
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Key takeaways:
- New 5-year DFS further supports adjuvant chemotherapy after nephroureterectomy for treatment of this patient population.
- Although not statistically significant, researchers also noted a slight OS benefit.
Gemcitabine and platinum chemotherapy administered after nephroureterectomy significantly improved OS among certain patients with upper tract urothelial carcinoma, updated results form a randomized phase 3 study showed.
Although OS data published in Journal of Clinical Oncology did not serve as the primary outcome measure of the trial, the new findings plus initially reported DFS data further supports the use of adjuvant chemotherapy among patients with upper tract urothelial cancer, according to researchers.
“What initially surprised us was the strength of the data read out. Our primary endpoint for the study was DFS at 3 years, but this was met at 2 years, which meant we closed the study early,” Alison Jane Birtle, MD, MBBS, MRCP, FRCR, honorary clinical professor and consultant oncologist at Rosemere Cancer Center at Royal Preston Hospital in the U.K., told Healio.
“In addition, the type of chemotherapy — whether gemcitabine/cisplatin ,or gemcitabine/carboplatin — did not matter, and both showed benefit,” she added. “POUT is the only randomized trial to test the hypothesis that chemotherapy given after nephroureterectomy will improve outcomes for patients.”
Background and methodology
The phase 3 POUT trial aimed to assess the efficacy of systemic platinum-based chemotherapy after nephroureterectomy among patients with upper tract urothelial carcinoma receiving treatment across 57 U.K. hospitals.
Researchers randomly assigned 261 patients (median age, 68.5 years; interquartile range IQR, 62-74.1) in a 1:1 ratio to surveillance (n = 129) or to four, 21-day cycles of chemotherapy (n = 132) with either 70 mg/m² cisplatin or IV carboplatin area under the curve 4.5 or 5 for glomerular filtration rate less than 50 mL/min only on day 1, followed by 1,000 mg/m² IV gemcitabine on days 1 and 8 of each cycle.
Patients received chemotherapy within 90 days after nephroureterectomy.
Most patients (94%) had stage pT2-T3 disease, and 91% of these patients also had stage N0 disease. Sixty-four percent of patients had a glomerular filtration rate of 50 mL/min or higher.
DFS served as the study’s primary endpoint.
Results
Healio previously reported results that showed a significant improvement in DFS with adjuvant chemotherapy (HR = 0.45; 95% CI, 0.3-0.68).
In addition, researchers reported 3-year DFS estimates of 71% (95% CI, 61-78) with adjuvant chemotherapy vs. 46% (95% CI, 36-56) with surveillance (absolute difference, 25%; 95% CI, 11-38).
Updated data showed 5-year DFS of 62% for adjuvant chemotherapy vs. 45% for the surveillance group (univariate HR = 0.55; 95% CI, 0.38-0.8). Restricted mean survival time appeared to be 18 months longer (95% CI, 6-30) in the chemotherapy arm as well.
Researchers also noted 5-year OS rates of 66% vs 57% (univariate HR = 0.68; 95% CI, 0.46-1) and a restricted mean survival time difference of 11 months (95% CI, 1-21).
Effects from treatment appeared consistent across chemotherapy regimens and disease stage, with treatment-related toxicities similar to previously reported data with no clinically relevant difference in quality of life between treatment arms.
Next steps
“We believe these new data further support the importance of giving adjuvant chemotherapy after nephroureterectomy for invasive [upper tract urothelial cancer],” Birtle told Healio. “Of note, recent trials of adjuvant immunotherapy in urothelial cancer have included small numbers of [upper tract urothelial cancer] patients who were denied chemotherapy in the control arm.
“The subgroup analyses of these trials cast significant doubt on the efficacy of immunotherapy as an alternative to chemotherapy in this setting,” she added. “The unanswered questions are around biomarkers — there is an ongoing study looking at who might benefit the most.”
For more information:
Alison Jane Birtle, MD, MBBS, MRCP, FRCR, can be reached at alison.birtle@lthtr.nhs.uk.
Perspective
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Stephanie A. Berg, DO
Discussion of adjuvant treatment options for patients with upper tract urothelial cancer (UTUC) will involve which “best” treatment to offer, especially in the era of two positive adjuvant immune checkpoint inhibitor (ICI) trials (Checkmate-274 and A031501/AMBASSADOR/KEYNOTE-123). I predict the debate will continue regarding carboplatin vs. immune checkpoint inhibition in UTUC and whether it should remain an option for those who refuse or are ineligible for cisplatin. These positive trials for ICIs had small UTUC populations and extrapolation of benefit is limited. Currently, the phase 2/3 ECOG study (EA8192, NCT04628676) is exploring the addition of durvalumab (Imfinzi, AstraZeneca) to chemotherapy versus chemotherapy alone in the perioperative setting for patients with UTUC. This study uses ddMVAC [dose-dense methotrexate, vinblastine, doxorubicin and cisplatin) as a backbone and one arm is included for patient’s ineligible for cisplatin, using durvalumab and gemcitabine. Also, the real-world trial, URANUS (NCT02969083) is currently enrolling in Europe to explore feasibility of UTUC treatments. Patients will be randomized to neoadjuvant or adjuvant chemotherapy (receiving 3 cycles of gemcitabine/cisplatin or ddMVAC) or will undergo RNU only. Both studies will complement POUT and provide us with a better understanding of patient management.
I expect that continued molecular testing defining the genetic landscape in UTUC will influence future trial design and lead to novel therapeutic combinations. Finally, incorporation of circulating tumor DNA, especially in the perioperative setting, may lead to better definition of the ‘best’ patient population who will or won’t benefit from these therapies in the shared decision-making process.
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