Phase 2 study of perioperative sacituzumab govitecan in combination with zimberelimab and domvanalimab for patients with muscle invasive bladder cancer ineligible or who refuse cisplatin-based chemotherapy: The PRISMA-1 study.

TPS884 Background: Neoadjuvant cisplatin-based chemotherapy (NACT) has demonstrated a 5-8% improvement in 5-year overall survival (OS) in patients (pts) with muscle invasive bladder cancer (MIBC). However, its routine implementation is still low due to concerns about toxicity/efficacy. Also, about 50% of pts are considered cisplatin ineligible and therefore unable to receive NACT. Immune-checkpoint inhibitors (ICI) and antibody drug conjugates (ADC) have demonstrated separately clinical activity in the perioperative setting and recently remarkable efficacy of ADC-ICIs combos has been shown in pts with advanced urothelial cancer. Therefore, combining ICIs with ADCs as a neoadjuvant therapy results an interesting approach. PRISMA-1 study will evaluate safety and efficacy of the Trop-2 directed ADC, sacituzumab govitecan (SG) in combination with the anti-PD1 zimberelimab (Z) and the anti-TIGIT domvanalimab (D) in MIBC. This study will also search for predictive biomarkers of response and will evaluate the role of ctDNA in the perioperative setting to better select for patients who need post operative treatment. Methods: PRISMA-1 study (NCT06133517) is a phase II, single arm, multicenter clinical trial that will enroll 70 adult pts with MIBC, [cT2-T4cN0-1cM0], ECOG PS 0-2, non-eligible or who refuse to receive NACT. The primary endpoint is pathological complete response (pCR) rate. Downstaging, relapse free survival and OS along with ctDNA clearance are some of the secondary endpoints. The study has two stages: First 8 pts will receive the combination of neoadjuvant SG+Z to confirm tolerability. Once safety has been confirmed additional 8 pts will receive the triplet SG+Z+D. If no dose limiting toxicities are observed recruitment will continue to enroll a total of 70 patients. Patients will receive three Q3W neoadjuvant cycles of Z (360 mg day 1) + D (1200 mg day 1) plus SG (7.5 mg/m2 days 1 & 8) followed by cystectomy. After surgery, only those pts who do not achieve a pCR or that achieving a pCR still have positive ctDNA will receive 12 additional cycles of adjuvant treatment with only Z + D. The remaining will be followed with serial ctDNA and imaging. Clinical trial information: NCT06133517 .