2366P - Phase I-II study of niraparib plus cabozantinib in patients with advanced urothelial/kidney cancer (NICARAGUA trial)

Background

Niraparib (N) is a (PARP)-1/-2 inhibitor (inh) and Cabozantinib (C) is a receptor tyrosine kinase (RTK) inhibitor that targets multiple RTKs (c-MET, TYRO3, AXL, MER). It has been proposed that aberrant c-MET activation could decrease response to PARP inhibitors (PARPi). Preclinical data show that c-Met inhibition renders cells more sensitive to PARPi. Safety of N + C was explored in advanced clear cell renal cell carcinoma or metastatic urothelial carcinoma (mUC) (Ph I. #GU-ASCO-22). We now report safety and efficacy in an expansion cohort of mUC (Ph II).

Methods

Multicenter, open-label Ph I-II study (NCT03425201). Patients (pts) received N/C 100/40 mg p.o. once daily in 28-day cycles. Pts with confirmed histopathological diagnosis of mUC (Ph II) previously treated with at least 2 previous regimens, one platinum-based, and ECOG PS 0-2, were included. Adequate bone marrow, liver and renal functions were required. No pre-molecular selection was assessed (DDR-gene mut or c-MET mut).

Results

The first interim analysis of 44 mUC pts is presented. Median age was 67 years and 98% of pts were male. All pts had received platinum-based treatment and 80% had received immunotherapy. Median number of administered cycles is 3 (range 1-18) and 13 pts are still on treatment at the time of this analysis. Disease control rate was 47.7% and ORR was 15.9%. With a median follow-up time of 5.9 months (range 1.8-19.5), median progression free survival (PFS) and overall survival were 3.8 and 8.7 months, respectively; 6 months PFS was 31%. Most frequent all grade adverse events (AEs), included: asthenia (71%), hypertension (43%), diarrhea (27%), constipation (27%), anemia (25%) and palmar-plantar erythrodysesthesia (23%). Most frequent grade 3 AEs were: asthenia (11%), hypertension (9%) and decreased appetite (9%).

Conclusions

N 100 mg/d + C 40 mg/d combination can be safely administered and has clinical efficacy (30% of pts are still on treatment) in a biomarker unselected heavily pretreated population.

Clinical trial identification

EudraCT 2017-004367-12, NCT03425201.

Editorial acknowledgement

Juan Luis Sanz (APICES).

Legal entity responsible for the study

Fundación CRIS.

Funding

GSK and Ipsen.

Disclosure

D.E. Castellano Gauna: Financial Interests, Personal, Advisory Board: Pfizer, Roche, BMS, Janssen, Astellas, MSD, Ipsen, AstraZeneca, Novartis, GSK; Financial Interests, Institutional, Local PI: Pfizer, Roche, MSD, BMS, AstraZeneca, Janssen, Astellas, Ipsen, Exelisis, Eisai, Lilly, Bayer, GSK, Clovis, QED Therapeutics; Non-Financial Interests, Personal, Other, Executive member: SOGUG (Spanish Oncology Genito-Urinary Group) Foundation. I. Duran Martinez: Financial Interests, Personal, Advisory Board, I have served as an advisor for this company in the last two years: Roche Genentech, MSD, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker, I have participated in different compensated educational activities sponsored by Jansen over the last two years: Jansen; Financial Interests, Personal, Invited Speaker, I have participated in different compensated educational activities sponsored by Pfizer over the last two years: Pfizer; Financial Interests, Personal, Advisory Board, I have collaborated as an advisor in different occasions over the last two years: Ipsen; Financial Interests, Personal, Invited Speaker, I have participated in different compensated educational activities sponsored by this company over the last two years: Ipsen, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, I have collaborated as an advisor for this company in the last two year: Merck; Financial Interests, Personal, Advisory Board, I have participated in different compensated advisory boards over the last two years: Astellas; Financial Interests, Personal, Advisory Board, I have collaborated as an advisor for this company over the last two years: Immunomedics, Inc.; Financial Interests, Personal, Invited Speaker, I have participated in educational activities sponsored by this company in the last two years: EUSA Pharma, MSD; Financial Interests, Personal, Invited Speaker, I have participated in educational activities sponsored by Novartis in the last 2 years: Novartis; Financial Interests, Personal, Invited Speaker, I have participated in compensated educational activities for this company in the last two years: Astellas; Financial Interests, Personal, Invited Speaker, I have participated in activities sponsored by this company as a guest speaker: Bayer; Financial Interests, Personal, Other, Bayer has covered expenses related to EAU 2023 including registration, travel and accommodation: Bayer; Financial Interests, Personal and Institutional, Research Grant, Roche has funded research in my institution to projects under my coordination: Roche Genentech; Financial Interests, Personal, Steering Committee Member, I serve as a member of a SC for a trial sponsored by this company: Immunomedics, Inc.; Financial Interests, Personal and Institutional, Research Grant, AZ has funded research conducted in my institution related to a project where I am the PI: AstraZeneca; Financial Interests, Institutional, Coordinating PI, I am leading a study (Investigator initiated) that is funded by Gilead and sponsored by the foundation of my department (FUPOCAN): Gilead; Non-Financial Interests, Leadership Role, I am the president of an independent cooperative group of GU Oncologist from the north of Spain: GO NORTE; Non-Financial Interests, Member of Board of Directors, I am member of the Board of directors since 2022: ASEICA; Non-Financial Interests, Member of Board of Directors, GUARD is a GU oncology cooperative group. I am a co-founder and member of the board of directors since 2023: GUARD. B. Mellado Gonzalez: Financial Interests, Personal, Other, Research Grant/Funding (Self), Speaker Bureau, Travel accommodation: Janssen, Roche, Astellas, Sanofi, Bayer; Financial Interests, Personal, Other, Speaker Bureau, Travel accommodation: Pfizer; Financial Interests, Personal, Other, Travel accommodation, Speaker Bureau: Ipsen; Financial Interests, Personal, Other, Speaker Bureau: BMS. M.A. Climent Duran: Financial Interests, Personal, Advisory Board: Roche, BMS, EUSA, Pfizer, Sanofi, Janssen, Astellas, Merck, Ipsen, MSD; Financial Interests, Personal, Invited Speaker: EUSA, Pfizer, Sanofi, Janssen, Astellas, Merck, Ipsen, BMS, Roche, MSD. X. Garcia Del Muro: Financial Interests, Personal, Advisory Board: Ipsen, EusaPharma, BMS, Pfizer, Roche, PharmaMar; Financial Interests, Personal, Invited Speaker: Lilly, Astellas Pharma, Eisai, Pfizer; Financial Interests, Institutional, Research Grant: AZ. N. Sala González: Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Invited Speaker: Ipsen, BMS; Financial Interests, Personal, Advisory Board: Merck. T. Alonso Gordoa: Financial Interests, Personal, Advisory Board: Ipsen, Pfizer, Roche, Sanofi, Bayer, Eisai, Novartis Advanced Accelerator Applications, Lilly, Bristol Myers Squibb, Astellas; Financial Interests, Personal, Invited Speaker: Janssen-Cilag; Non-Financial Interests, Project Lead: Pfizer, Ipsen. E. Sevillano Fernandez: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Institutional, Research Grant: Pfizer, Roche; Financial Interests, Personal, Invited Speaker: Astellas, Pfizer. F.X. Real: Financial Interests, Personal, Research Grant: Janssen. N. Malats: Non-Financial Interests, Personal, Advisory Board, Member of the study: CNIO. A. Font Pous: Financial Interests, Institutional, Advisory Board: Pfizer, Bayer, Astellas. All other authors have declared no conflicts of interest.