Improved Disease-Free Survival With Adjuvant Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Cancer: Final Results of the POUT Trial

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. POUT was a phase III, randomized, open-label trial, including 261 patients with muscle-invasive or lymph node–positive, nonmetastatic upper tract urothelial cancer (UTUC) randomly assigned after radical nephroureterectomy to platinum-based chemotherapy (132) or surveillance (129). Primary outcome analysis demonstrated that chemotherapy improved disease-free survival (DFS). At that time, the planned secondary outcome analysis of overall survival (OS) was immature. By February 2022, 50 and 67 DFS events had occurred in the chemotherapy and surveillance groups, respectively, at a median follow-up of 65 months. The 5-year DFS was 62% versus 45%, univariable hazard ratio (HR), 0.55 (95% CI, 0.38 to 0.80, P = .001). The restricted mean survival time (RMST) was 18 months longer (95% CI, 6 to 30) in the chemotherapy arm. There were 46 and 60 deaths in the chemotherapy and control arms, respectively. The 5-year OS was 66% versus 57%, with univariable HR, 0.68 (95% CI, 0.46 to 1.00, P = .049) and RMST difference 11 months (95% CI, 1 to 21). Treatment effects were consistent across chemotherapy regimens (carboplatin or cisplatin) and disease stage. Toxicities were similar to those previously reported, and there were no clinically relevant differences in quality of life between arms. In summary, although OS was not the primary outcome measure, the updated results add further support for the use of adjuvant chemotherapy in patients with UTUC, suggesting long-term benefits.


INTRODUCTION
Primary analysis of the POUT trial, demonstrating improved disease-free survival (DFS), supports the use of adjuvant gemcitabine:platinum chemotherapy after nephroureterectomy for patients with muscle invasive upper tract urothelial cancer (renal pelvis or ureter, UTUC). 1 At the time of initial publication, overall survival (OS) data, a key secondary end point, were immature.We present updated DFS and a prespecified final analysis of OS and other secondary end points.
We present updated results for the primary end point (DFS) and the secondary end points: metastasis-free survival (MFS), disease-specific survival (DSS), and quality of life (QoL; European Organisation for Research and Treatment of Cancer Quality of Life questionnaire and EQ-5D at 12 and 24 months).In addition, time to second primary tumor in the bladder (TSPB) and late toxicity (6-24 months, Common Terminology Criteria for Adverse Events [CTCAE] v4, with censoring 3 months before recurrence) are reported and we describe subsequent treatments (exploratory end point).
TSPB was defined as time from random assignment to the date of diagnosis of second bladder primary (muscle-invasive or non-muscle-invasive), censored at diagnosis of other second primary, date last known to be event-free, or death.

Statistical Analysis
In addition to methods described previously, 1 where nonproportional hazards were evident from tests of Schoenfeld Abbreviations: N, node; T, tumor.
a Chemotherapy regimen to be used in the event of random assignment to the chemotherapy arm was specified before random assignment.
residuals, 2 restricted mean survival time (RMST) was used to estimate differences between arms in average survival time within a 9-year period without assuming a constant hazard ratio. 3Analysis was by intention-to-treat with the exception of toxicity (analyzed by treatment received).

Participants
Two hundred sixty-one patients (132 chemotherapy; 129 surveillance) were randomly assigned between June 2012 and November 2017 at 57 centers.By February 2022, the median follow-up was 65 months (IQR, 60-84).One participant (chemotherapy arm) withdrew consent for data use and was excluded from analyses.Table 1 shows baseline characteristics.

Disease Events
There were 50 and 67 DFS events in the chemotherapy and surveillance groups, respectively.Risk of recurrence or death was reduced in patients allocated to chemotherapy (

DISCUSSION
Primary results from POUT have already changed practice on the basis of the DFS benefit. 4The validity of changing practice on the basis of DFS alone has been reaffirmed by recent regulatory approvals for adjuvant nivolumab in invasive urothelial cancer, including UTUC. 4 Although preventing relapse is of likely clinical benefit in its own right, one key purpose of adjuvant therapy is to delay or prevent cancer death.Because of the rarity of UTUC, it was impractical to conduct a trial with OS as a primary end point.Furthermore, since POUT was stopped early on the basis of superior DFS with chemotherapy, power for OS analysis was reduced.Nevertheless, a statistically significant OS advantage was seen in univariable analysis (P 5 .049)and, although nonsignificant, multivariable modeling showed a consistent positive trend.The presence of nonproportional hazards may also affect the power of these analyses 3 ; RMST results, which account for this, show a statistically significant OS benefit of 11 months over a 9-year period, with the peak benefit between 3 and 4 years.Combined with improvements in MFS and DSS, these results add weight to the sustained DFS benefit confirmed here.
Although carboplatin is considered by many to be less effective than cisplatin in urothelial cancer, 5 nephroureterectomy (by its nature) results in reduced renal function.Hence, it was important, for generalizability of results, to include a safe option for delivering platinum-based chemotherapy for those with impaired renal function.Subgroup results from the POUT primary analysis left some uncertainty about the value of carboplatin for those patients. 1Although not powered for a formal test of interaction, updated HRs (Fig 2 ) suggest a consistent benefit of chemotherapy, regardless of the regimen, supporting inclusion of these patients in the treatment recommendation.Other recent data also suggest that the utility of carboplatin compared with cisplatin in urothelial cancer has been underestimated. 6,7e POUT primary analysis showed acceptable levels of acute toxicity with chemotherapy, in line with previous reports. 8In the current analysis, data on both clinician-reported toxicity and patient-reported QoL provide reassurance that there are no important long-term adverse impacts, which might offset the benefits.Systemic therapy on relapse was less frequent in those who received adjuvant chemotherapy than those in the surveillance group.This may reflect the lack of effective, approved second-line therapies in the UK during most of the POUT follow-up period.By contrast, control arm patients could access frontline platinum-based chemotherapy on relapse.We speculate that this difference between arms is unlikely to have had any significant impact on the trial end points.
While chemotherapy reduces time to metastasis, it appeared to have no impact on the evolution of second primary formation in the bladder.0][11][12] The pattern here may suggest that, particularly, later-forming tumors could be the result of a new, in situ oncogenic process; notwithstanding, such temporal relationships remain to be fully elucidated.
In summary, updated outcomes from the POUT trial add further support to the value of adjuvant systemic gemcitabine:platinum combination chemotherapy after nephroureterectomy for UTUC.

FIG 2 .
FIG 2. Forest plots showing treatment effects according to key baseline factors and planned chemotherapy regimen for (A) DFS and (B) OS.DFS, disease-free survival; HR, hazard ratio; OS, overall survival.

TABLE 1 .
Participant and Tumor Characteristics at Trial Entry CTCAE grade ≥3 rates between 6 and 24 months were similar in both groups (40 of 240, 16.7%, Appendix TableA3).No important differences in QoL were observed (Appendix TableA4).

TABLE A1 .
Disclosures provided by the authors are available with this article at DOI https://doi.org/10.1200/JCO.23.01659.Details of Treatment for Recurrence Percentage of patients with a recurrence treated in this way (ie, denominator is the number of patients who experienced a recurrence of any kind).b Categories are not mutually exclusive since patients might have received multiple treatments. a

TABLE A3 .
Late Toxicity Reported Between 6 and 24 Months Postrandomization (censored within 3 months of progression) a One grade 5: death because of gastric bleeding.© 2024 by American Society of Clinical Oncology Birtle et al

TABLE A4 .
Differences Between Treatment Groups in Mean Functional and Symptomatic Quality-of-Life Scales (EORTC-QLQ-C30) Reported at 12 and 24 Months Postrandomization