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. 2020 May 26;15(5):e0233260.
doi: 10.1371/journal.pone.0233260. eCollection 2020.

Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies

Laura S Graham  1   2 , Bruce Montgomery  1   3 , Heather H Cheng  1   2 , Evan Y Yu  1   2 , Peter S Nelson  1   2   4 , Colin Pritchard  5 , Stephanie Erickson  6 , Ajjai Alva  6 , Michael T Schweizer  1   2
Affiliations

Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies

Laura S Graham et al. PLoS One. .

Abstract

Background: While response rates to anti-PD1 therapy are low in unselected metastatic castration resistant prostate cancer (mCRPC) patients, those with inactivating mutations in mismatch repair (MMR) genes (i.e. MMR deficiency; MMRd) or microsatellite instability (MSI) are thought likely to respond favorably. To date, there is limited published data on this biologically distinct and clinically relevant subgroup's natural history and response to treatment.

Methods: We retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic prostate cancer (PC). Clinical and pathologic characteristics at the time of diagnosis as well as response to standard therapies and immune checkpoint therapy were abstracted. Descriptive statistics, including PSA50 response (≥50% decline in PSA from baseline) and clinical/radiographic progression free survival (PFS), are reported.

Results: 27 men with MMRd and/or MSI-high metastatic PC were identified. 13 (48%) men had M1 disease at diagnosis and 19 of 24 (79%) men that underwent prostate biopsy had a Gleason score ≥8. Median overall survival from time of metastasis was not reached (95% CI: 33.6-NR mos) after a median follow up of 33.6 mos (95% CI: 23.8-50.5 mos). Seventeen men received pembrolizumab, of which 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and the estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who achieved a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression at a median follow up of 12 months (range 3-20 months).

Conclusions: MMRd PC is associated with high Gleason score and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high. Our study is limited by small sample size, and more research is needed to identify additional factors that may predict response to immunotherapy.

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Conflict of interest statement

BM has received research funding to his institution from Clovis, Janssen, Astellas, Beigene and AstraZeneca. HHC has served as a paid consultant to AstraZeneca and received research funding to her institution from Clovis Oncology, Janssen, Medivation, Sanofi Aventis and Color Genomics. EYY has served as a paid consultant and/or received an honorarium from Abbvie, Advanced Accelerator Applications, Amgen, Astrazeneca, Bayer, Churchill, Clovis, Dendreon, EMD Serono, Genentech, Incyte, Janssen, Lilly, Merck, Pharmacyclics, QED, Sanofi-Genzyme, Seattle Genetics, Tolmar and has received research funding to his institution from Bayer, Daiichi-Sankyo, Dendreon, Genentech, Merck, Pharmacyclics, Seattle Genetics and Taiho. PSN has served as a paid consultant to Janssen, Astellas and Bristol Myers Squibb. CP has served as a paid consultant to AstraZeneca and Promega. AA has served as a paid consultant to Merck, Astra Zeneca, BMS and received research funding to his institution from Prometheus, Clovis, Merck, Astra Zeneca, BMS, Celgene, Arcus Biosciences, Ionnis Pharmaceuticals and Esanik. MTS has served as a paid consultant to Janssen and received research funding to his institution from Janssen, AstraZeneca, Pfizer, Madison Vaccines and Hoffman-La Roche. All other authors have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Figures

Fig 1
Fig 1. Best PSA response on docetaxel in men with MMRd/MSI-H PC.
Best % PSA change from baseline following treatment with docetaxel. Red = docetaxel used for hormone-sensitive disease. Black = docetaxel used for castration-resistant disease.
Fig 2
Fig 2. Best PSA response on second generation hormonal agents in men with MMRd/MSI-H PC.
Best % PSA change from baseline following treatment with abiraterone (A) and enzalutamide (B). Red = agent used for hormone-sensitive disease. Black = agent used as 1st line treatment for mCRPC. Blue = agent used as 2nd line agent for mCRPC.
Fig 3
Fig 3. Best PSA response on pembrolizumab in men with MMRd/MSI-H PC.
Best % PSA change from baseline following treatment with pembrolizumab. Black = hypermutated (±10 mut/Mb). Blue = not hypermutated. Red = unknown mutational load.
Fig 4
Fig 4. Progression free survival on pembrolizumab in men with MMRd/MSI-H PC.
PSA PFS (A) and Radiographic PFS (B).
See this image and copyright information in PMC

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Supplementary concepts