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| 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. | ||||||||||||
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| 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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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| 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 |
| MSH2 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 |