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Published on: March 6, 2018
Efficacy of Anti-PD-(L)1 Immunotherapy in Patients with DNA Mismatch Repair-deficient Metastatic Castration-resistant
Sandra van Wilpe1, Tarek Taha2, Emily C Rothmann3
1Medical Oncology Department, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
Background And Objective:
Up to 5% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbour loss-of-function alterations in mismatch repair genes (dMMR) resulting in microsatellite instability (MSI-H). Data on the efficacy of immune checkpoint inhibitors (ICIs) in dMMR mCRPC are limited, and reimbursement for these agents is not universally available.
Methods:
We performed an international, multicentre, retrospective study to investigate the efficacy of anti-PD-(L)1 monotherapy in dMMR mCRPC. dMMR was defined as MMR protein loss on immunohistochemistry (IHC), and/or a deleterious alteration in an MMR gene or MSI-H status according to polymerase chain reaction analysis or next-generation sequencing. The primary endpoint was progression-free survival (PFS).
Key Findings And Limitations:
Between July 2016 and July 2024, 93 patients with a median age of 70 yr (range 46-90) started anti-PD-(L)1 treatment. Patients were classified as dMMR on the basis of IHC results (n = 37, 40%), genomic alterations in MMR genes (n = 55, 59%), and/or an MSI-H phenotype (n = 64, 69%). Among evaluable patients according to Response Evaluation Criteria in Solid Tumours v1.1, the objective response rate was 46% (n = 84; 95% confidence interval [CI] 35-58%). A prostate-specific antigen decline ≥50% was observed in 60% of evaluable patients (n = 68; 95% CI 48-72%). Median PFS across the entire cohort was 7.7 mo (95% CI 5.3-12.4), with 1-yr, 2-yr, and 3-yr PFS rates of 39%, 27%, and 26%, respectively. Median overall survival was 27.0 mo (95% CI 17.7-43.5). PFS was significantly longer for patients with positive dMMR status on two or more tests than for patients with just one positive dMMR test.
Conclusions And Clinical Implications:
These data confirm the efficacy of anti-PD-(L)1 therapy in patients with dMMR mCRPC and warrant consideration of reimbursement for anti-PD-(L)1 agents in dMMR mCRPC by health authorities.
Insights
Immune checkpoint inhibitors show efficacy in metastatic castration-resistant prostate cancer with DNA mismatch repair deficiency (dMMR mCRPC). These findings support reimbursement for anti-PD-(L)1 therapies in this patient group.
Area of Science:
- Oncology
- Immunotherapy
- Genetics
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) affects a subset of patients with DNA mismatch repair deficiency (dMMR), leading to microsatellite instability-high (MSI-H) status.
- Data regarding the effectiveness of immune checkpoint inhibitors (ICIs) in dMMR mCRPC are scarce, impacting treatment accessibility and reimbursement.
Purpose of the Study:
- To evaluate the efficacy of anti-PD-(L)1 monotherapy in patients with dMMR mCRPC.
- To provide evidence supporting the use and reimbursement of ICIs for dMMR mCRPC.
Main Methods:
- An international, multicenter, retrospective study involving 93 patients with dMMR mCRPC treated with anti-PD-(L)1 monotherapy.
- dMMR status was determined by immunohistochemistry (IHC), gene sequencing, or polymerase chain reaction (PCR) for MSI-H.
- Primary endpoint was progression-free survival (PFS); objective response rate (ORR) and overall survival (OS) were also assessed.
Main Results:
- The objective response rate (ORR) was 46% and a ≥50% prostate-specific antigen decline was observed in 60% of evaluable patients.
- Median progression-free survival (PFS) was 7.7 months, with 3-year PFS rates of 26%. Median overall survival (OS) was 27.0 months.
- Patients with dMMR confirmed by two or more diagnostic methods showed significantly longer PFS compared to those with a single positive test.
Conclusions:
- Anti-PD-(L)1 therapy demonstrates significant efficacy in patients with dMMR mCRPC.
- These findings support the consideration of reimbursement for anti-PD-(L)1 agents in this specific patient population by health authorities.
