LBA5 - A randomized phase III trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA)

Background

The management of muscle-invasive bladder cancer (MIBC) for cisplatin-eligible patients (pts) includes neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). We evaluated durvalumab (D) in combination with NAC followed by RC and adjuvant D in pts with MIBC.

Methods

NIAGARA (NCT03732677) is a phase 3, randomized, open-label, multicenter trial that enrolled cisplatin-eligible pts with MIBC (cT2-T4aN0/1M0) planned for RC. Pts were randomized (1:1) to receive either neoadjuvant D (1500 mg IV Q3W) and NAC (cisplatin + gemcitabine IV Q3W) for 4 cycles followed by RC then adjuvant D monotherapy (1500 mg IV Q4W) for 8 cycles (D arm), or NAC followed by RC alone (comparator arm). Stratification factors were clinical tumor stage (cT2N0 vs >cT2N0), renal function (CrCl ≥60 mL/min vs ≥40 to <60 mL/min), and PD-L1 status (high vs low/negative). Dual primary endpoints were event-free survival (EFS) and pathologic complete response (pCR). Overall survival (OS) was an alpha controlled secondary endpoint. Here, we present a pre-planned interim analysis of EFS and OS (data cutoff [DCO] Apr 2024). The pCR formal analysis (DCO Jan 2022) was not statistically significant.

Results

A total of 1063 pts were randomized (533 D arm; 530 comparator arm). Median EFS follow up in censored pts was 42.3 months (range 0.03–61.3). EFS and OS were significantly longer in the D arm vs comparator arm (EFS HR 0.68 [95% CI 0.56–0.82], p<0.0001; OS HR 0.75 [95% CI 0.59–0.93], p=0.0106). RC was completed in 88% (D arm) and 83% (comparator arm) of pts. Post RC, 383/469 pts (82%) initiated adjuvant D. Grade 3/4 treatment-related adverse events (AEs) occurred in 41% of pts in each arm. AEs leading to discontinuation of neoadjuvant treatment were reported in 15% of pts in each arm; 8% discontinued adjuvant D due to AEs. Overall treatment-related deaths occurred in 0.6% of pts in each arm.

Conclusions

Perioperative D plus NAC demonstrated a statistically significant and clinically meaningful improvement in EFS and OS vs NAC alone and addition of neoadjuvant D did not compromise the ability to complete RC in pts with MIBC. The safety profile was consistent with the individual agents.

Clinical trial identification

NCT03732677; November 06, 2018.

Editorial acknowledgement

Editorial and medical writing support was provided in accordance with Good Publication Practice guidelines by Lewis Cawkwell, PhD, of Parexel, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

T.B. Powles: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Merck, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, MSD; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Roche, Pfizer, MSD, AstraZeneca, Ipsen; Financial Interests, Personal, Other, Sponsorship for Uromigos Podcast: Mashup Ltd; Financial Interests, Institutional, Other, honoraria: Gilead; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck, MSD, Seattle Genetics, Novartis, Pfizer, Merck Serono, Astellas, Johnson & Johnson, Eisai; Financial Interests, Institutional, Other, Honoraria: Gilead. M.S. van der Heijden: Financial Interests, Institutional, Advisory Board: AstraZeneca, BMS, Janssen, MSD, Seagen, Pfizer, Astellas; Financial Interests, Institutional, Funding, Investigator-initiated trial: BMS, Roche, AstraZeneca, 4SC, MSD; Financial Interests, Institutional, Steering Committee Member, Local PI + SSC member: BMS, AstraZeneca, MSD, Seagen; Financial Interests, Institutional, Steering Committee Member, Local PI + study co-PI: Janssen. M.D. Galsky: Financial Interests, Personal, Advisory Board: Janssen, Merck, GSK, Eli Lilly, Astellas, Genentech, Bristol Myers Squibb, Pfizer, EMD Serono, AstraZeneca, Seagen, Incyte, Alligator, AbbVie, Asieris, Bicycle, Gilead, Curis, Fujifilm; Financial Interests, Personal, Other, Consultant: Rappta Therapeutics; Financial Interests, Personal, Invited Speaker: Veracyte; Financial Interests, Institutional, Steering Committee Member: Merck, Genentech, Bristol Myers Squibb,; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Jazz; Financial Interests, Institutional, Local PI: Seagen. H. Al-Ahmadie: Other, Consulting fees: AstraZeneca, Paige.AI, Pfizer. J.J. Meeks: Other, Honoraria: Merck, AstraZeneca, Janssen, BMS, UroGen, Prokarium, Pfizer, Seagen/Astellas, Olympus, Ferring, Carden Jennings, MJ Health. H. Nishiyama: Other, Funding: AstraZeneca; Other, Grants: Chugai Pharma, Ono Pharmaceutical, Bayer; Other, Consulting fees: Ono Pharmaceutical, Pharma, Merck Sharp & Dohme (MSD), Janssen; Other, Honoraria: Astellas, Merck Sharp & Dohme (MSD), Nippon Kayaku Co.Ltd., Merck Biopharma Co.Ltd., AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb (BMS). L. Antonuzzo: Other, Honoraria: AstraZeneca, Roche, Astellas, Novartis, MSD, BMS, Ipsen, Merk Serono, Amgen, Bayer; Other, meeting/travel: AstraZeneca, Novartis, Ipsen, Merk Serono; Other, Research funding: Novartis, AstraZeneca. P. Wiechno: Other, Consulting fees: Astellas, AstraZeneca, Bayer, MSD, BMS, Novartis, Pfitzer; Other, Honoraria: Astellas, AstraZeneca, Bayer, MSD, BMS, Novartis, Pfitzer; Other, Advisory Board: Astellas, AstraZeneca, Bayer, MSD, BMS, Novartis, Pfitzer. A.G. Kann: Other, Honoraria &travel: AstraZeneca. C. Suarez Rodriguez: Other, Funding: Ipsen; Other, Consulting fees: BMS, Pfizer, Roche, Astellas, Ipsen, Sanofi, Bayer, MSD; Other, Honoraria: BMS, Pfizer, Roche, Astellas, Ipsen; Other, Payment for expert testimony: BMS, Pfizer, Roche, Astellas, Ipsen; Other, Travel/Accommodation/Expenses: BMS, Pfizer, Roche. F. Roghmann: Other, Consulting fees: AstraZeneca, BMS, Roche, MSD, Merck Serono, Janssen, Pfizer, Bayer; Other, Travel support: Janssen, Merck Serono, AstraZeneca. M. Ozguroglu: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Steering Committee Member: Astellas; Financial Interests, Personal, Steering Committee Member, Steering Committee in Luminance, Pacific 8 trials: AstraZeneca; Financial Interests, Personal, Other, IASLC Lung cancer conference in Chicago: Regeneron. J. Armstrong: Financial Interests, Stocks/Shares: AstraZeneca. S. Ho: Financial Interests, Stocks/Shares: AstraZeneca. S. Hois: Financial Interests, Stocks/Shares: AstraZeneca. J. Catto: Other, Grants: Roche; Other, Consulting fees: AstraZeneca, BMS, Gilead, QED Therapeutics, Oche, Ferring, Steba biotech, UroGen, Janssen, Photocure; Other, Honoraria: BMS, AstraZeneca, Roche; Other, Trustee: Fight Bladder Cancer UK, Weston Park Cancer Charity. All other authors have declared no conflicts of interest.