ASCO GU 2020: Adjuvant Options in High-Risk Disease After Primary Intervention

San Francisco, California (UroToday.com) The adjuvant setting post-cystectomy is a critical opportunity to improve disease-free survival (DFS) and overall survival (OS) for patients with high-risk urothelial bladder cancer (UBC). Adjuvant treatment in UBC, however, is a complicated prospect due to competing risks. Approximately 43% of patients will be cured with local therapy (radiation or cystectomy). This means that adjuvant therapy will be exposing almost half of the patients treated to treatment-related toxicity with no possibility for benefit. The benefit of adjuvant cisplatin-based combination chemotherapy in UBC is a 23% reduction in mortality (hazard ratio [HR] = 0.77, 95% confidence interval 0.65-0.91) as reported in a meta-analysis of 949 patients from 9 trials. Whether patients who are cisplatin-ineligible or have residual disease after neoadjuvant chemotherapy (NAC) benefit from adjuvant treatment is less clear.

Dr. Matthew Galsky presented the following provocative questions regarding adjuvant therapy for UBC:

  • Does adjuvant chemotherapy cure patients?
  • Can we identify patients who need treatment?
  • Can we identify patients who benefit from treatment?
  • Are we paying attention to the biology?

Adjuvant therapy can improve DFS and OS through two distinct mechanisms: curing more patients and prolonging time to recurrence. Both mechanisms will lead to improved HR, but HR does not capture whether more patients are being cured. One must look at the survival curves to make this distinction. Using adjuvant therapy in colon cancer as an example, Dr. Galsky noted that the OS curve for adjuvant therapy does not cross the control arm, suggesting that adjuvant therapy is indeed curing patients.

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The question of who needs adjuvant therapy in UBC is more straightforward. High-risk pathology-based criteria have been defined based on rates of long-term DFS and OS. Among patients who did not receive NAC, compared to patients with organ-confined disease at cystectomy (DFS ~80%), those with extra-vesical disease have an inferior DFS (~55%); DFS for patients with lymph node disease is even lower (~35%). Similarly, in patients who received NAC, those with residual disease have a much lower long-term OS (~25%) compared to those who achieved pathologic complete response (~70%).

The question of who benefits from adjuvant therapy is less clear. Data suggest that patients with DNA damage repair (ATM, RB1, FANCC) alterations may derive greater benefit from NAC compared to patients who are wild-type in these genes.

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Based on efficacy data for Erdafitinib in patients with metastatic UBC and an FGFR alteration, investigators designed the PROOF 302 study (NCT04197986) testing the FGFR inhibitor Infigratinib versus placebo in high-risk patients post-cystectomy who have an FGFR3 alteration. This study is ongoing.

Emerging data suggest that paying attention to disease biology can inform treatment responses in the adjuvant setting. Assuming that a drug will be effective in the adjuvant setting because it was effective in the neoadjuvant or metastatic setting ignores biological factors such as tumor seeding, dormancy, and colonization. Perhaps reflective of this different biology pre- and post-cystectomy, a growing body of data suggests that immunotherapy may be more effective in the neoadjuvant than the adjuvant setting.

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Dr. Galsky concluded by urging the audience to review a recent publication describing expert opinion on optimal endpoints in UBC adjuvant clinical trials.2

Presented by: Matthew Galsky, MD, is a Medical Oncologist, Professor of Medicine, Director of Genitourinary Medical Oncology, Director of the Novel Therapeutics Unit, and Co-Director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai

Written by: Jacob Berchuck, MD, Medical Oncology Fellow at the Dana-Farber Cancer Institute (Twitter: @jberchuck) at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

References:

  1. Sternberg CN, et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 2015 Jan;16(1):76-86.
  2. Apolo AB, Eligibility and Radiologic Assessment in Adjuvant Clinical Trials in Bladder Cancer. JAMA Oncol. 2019 Oct 31:1-9.
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