Reference Detail

Ref Type

Journal Article

PMID

(39293514)

Authors

van Wilpe S, Kloots ISH, Slootbeek PHJ, Brok MD, Westdorp H, Franken MD, Coskunturk M, Osinga T, Bloemendal H, Adema G, Smeenk RJ, Nagarajah J, van Ipenburg J, Kroeze LI, Ligtenberg MJL, Schalken J, Gerritsen WR, Mehra N

Title

Ipilimumab with Nivolumab in molecular-Selected patients with castration-resistant PRostate cancer: primary analysis of the Phase 2 INSPIRE trial.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology			2024 Sep 10		Ann Oncol

URL

Abstract Text

Metastatic castration-resistant prostate cancer (mCRPC) typically exhibits resistance to immune checkpoint inhibitors (ICIs). However, a subset of mCRPC patients displays a more immunogenic profile. This study examines efficacy and safety of dual ICI therapy in molecularly selected mCRPC.This single-arm, phase II trial, included 69 molecularly selected mCRPC patients with mismatch repair deficiency (MMRd), non-synonymous tumour mutational burden ≥7.1 muts/Mb (hTMB), a BRCA2 mutation (BRCAm), or biallelic CDK12 inactivation (CDK12i). Efficacy was assessed in ICI-naïve patients (cohort A) with RECIST1.1 (A1) and PCWG3 (A2) measurable disease. Safety was evaluated in cohorts A and B (prior ICI monotherapy). Treatment included nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 cycles, followed by nivolumab 480 mg every 4 weeks for up to 1 year. The primary endpoint was disease control rate beyond 6 months (DCR>6), aiming to surpass a DCR>6 of 22%.Patients initiated treatment between January 2021 and February 2024. Cohort A included 65 patients. Of these, 21 had MMRd (32%), 8 hTMB (12%), 20 BRCAm (31%), and 16 CDK12i (25%). DCR>6 was achieved in 38% (95% CI 27-51), and was highest in MMRd (81%), followed by hTMB (25%), CDK12i (19%), and BRCAm (15%). Objective and PSA50 response rates in cohort A were 38% (95% CI 22-55) and 47% (95% CI 34-60), respectively. Median progression-free survival was 4.0 months (95% CI 3.5-12.0) in cohort A, and 32.7 months (95% CI 21.8-NR) in MMRd patients. Treatment-related adverse events (TRAEs) led to permanent discontinuation in 14 of 69 patients (20%). Grade ≥3 TRAEs occurred in 48% of patients, with diarrhoea and elevated transaminases each in 10%. There was one treatment-related death due to a bowel perforation and a second following euthanasia after grade 4 toxicity.This trial of dual ICIs in molecularly selected mCRPC met its primary endpoint, showing DCR>6 in 40% of patients. Dual ICIs exhibited modest responses in the hTMB, BRCAm and CDK12i subgroups, but demonstrated exceptional efficacy in MMRd.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MSH6 negative	prostate adenocarcinoma	predicted - sensitive	Ipilimumab + Nivolumab	Case Reports/Case Series	Actionable	In a Phase II trial (INSPIRE), treatment with Yervoy (ipilimumab) and Opdivo (nivolumab) in patients with metastatic prostate adenocarcinoma resulted in a disease control rate (DCR) at 6 mo of 38%, objective response rate (ORR) of 38% (14/37), and median progression-free survival (mPFS) of 4.0 mo in the overall efficacy cohort, and a DCR at 6 mo of 81%, ORR of 75% (9/12, all partial responses), and mPFS or 32.7 mo in patients with mismatch repair deficiency (dMMR) (PMID: 39293514).	39293514