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•Pembrolizumab is currently only FDA-approved for men with microsatellite instability (MSI)–high or mismatch repair–deficient (dMMR) status. The authors evaluated the clinical efficacy of pembrolizumab in 48 heavily pretreated patients with metastatic castration-resistant prostate cancer. Pembrolizumab was associated with ≥50% PSA decline in 8 patients, including a dramatic ≥90% PSA response in 4 patients. Of the 4 patients with a dramatic response, 2 had LRP1b mutations.
•Although this is a small, retrospective, single-institution study, the authors report the interesting finding of pembrolizumab achieving dramatic and durable responses in select patients with LRP1b mutations, potentially enriching checkpoint inhibitor responsiveness in prostate cancer.
– Paul Hampel, MD
BACKGROUND
Pembrolizumab is approved for patients with metastatic, microsatellite instability (MSI)-high or mismatch repair-deficient (dMMR) solid tumors. However, very few men with prostate cancer were included in these initial studies.
METHODS
We performed a single institution retrospective review of men with metastatic castrate-resistant prostate cancer (mCRPC) who were treated with pembrolizumab. The primary objective was to describe the clinical efficacy of pembrolizumab associated with patient and genomic characteristics.
RESULTS
We identified 48 men who received ≥1 cycle of pembrolizumab for mCRPC. Of these, 94% (45/48) had ≥3 prior lines of therapy for mCRPC. Somatic tumor sequencing was available in 18/48 men (38%). We found that 17% (8/48) had a ≥50% confirmed PSA decline with pembrolizumab, and 8% (4/48) had a ≥90% PSA decline with durations of response ranging from 3.1 to 16.3 months. Two of these four men had mutations in LRP1b, one of whom also had MSH2 loss and was MSI-H and TMB-high. Despite prior progression on enzalutamide, 48% (23/48) of men were treated with concurrent enzalutamide. The median PSA progression-free-survival was 1.8 months (range 0.4-13.7 months), with 31% of patients remaining on pembrolizumab therapy and 54% of men remain alive with a median follow-up of 7.1 months.
CONCLUSIONS
In a heavily pretreated population of men with mCRPC, pembrolizumab was associated with a ≥50% PSA decline in 17% (8/48) of men, including a dramatic ≥90% PSA response in 8% (4/48), two of whom harbored pathogenic LRP1b mutations suggesting that LRP1b mutations may enrich for PD-1 inhibitor responsiveness in prostate cancer.
Pembrolizumab in Men With Heavily Treated Metastatic Castrate-Resistant Prostate Cancer
Cancer Med 2019 Jul 03;[EPub Ahead of Print], MD Tucker, J Zhu, D Marin, RT Gupta, S Gupta, WR Berry, S Ramalingam, T Zhang, M Harrison, Y Wu, P Healy, S Lisi, DJ George, AJ Armstrong
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