Pembrolizumab in Patients With Heavily Treated Metastatic Castration-Resistant Prostate Cancer

[Balsam01]

TAKE-HOME MESSAGE

•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

[NPfisherman]

LRP1b is a member of the LDL family--see below:

genecards.org/cgi-bin/cardd...

Interesting, since it is part of my philosophy regarding PCA--the 4 Horsemen--Cholesterol, Glycolysis, Inflammation, and Hormones. It is good to know they are finding other gene malformations that Keytruda can be effective on in controlling cancers.

Thanks for posting the science, Balsam01....

Don Pescado

[j-o-h-n in reply to NPfisherman]

4 Horsemen, Cholesterol, Glycolysis, Inflammation, and Hormones. Did they also play for Notre Dame?

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 08/13/2019 6:28 PM DST

[NPfisherman in reply to j-o-h-n]

Go win one for the Gipper....LOL...

Fish

[j-o-h-n in reply to NPfisherman]

Did you say "REAPER"?🤢

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 08/13/2019 7:29 PM DST

[NPfisherman in reply to j-o-h-n]

NO !!!!!! JOHN....I am gonna take a hatpin to Dolly for that one....

Fish

[j-o-h-n in reply to NPfisherman]

youtube.com/watch?v=l7N2wss...(Not working as expected?)

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 08/13/2019 7:41 PM DST