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. 2019 Aug;8(10):4644-4655.
doi: 10.1002/cam4.2375. Epub 2019 Jul 3.

Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer

Matthew D Tucker  1 , Jason Zhu  1 , Daniele Marin  2 , Rajan T Gupta  2   3 , Santosh Gupta  3 , William R Berry  1   3 , Sundhar Ramalingam  1   3 , Tian Zhang  1   3 , Michael Harrison  1   3 , Yuan Wu  4 , Patrick Healy  4 , Stacey Lisi  5 , Daniel J George  1   3 , Andrew J Armstrong  1   3   6
Affiliations

Pembrolizumab in men with heavily treated metastatic castrate-resistant prostate cancer

Matthew D Tucker et al. Cancer Med. 2019 Aug.

Abstract

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.

Keywords: LRP1b; genomic profiling; mCRPC; pembrolizumab; prostate cancer.

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Conflict of interest statement

Jason Zhu reports personal fees from Bayer, outside the submitted work. Tian Zhang reports grants from Acerta, Novartis, Merrimack, Abbvie/Stemcentrx, Merck, Regeneron, Exelixis, Janssen, Pfizer, OmniSeq, and Personal Genome Diagnostics; services on speaker's bureau and advisory boards for Genentech/Roche, Exelixis, Sanofi‐Aventis; services on advisory board for Janssen, Astra Zeneca, Pfizer, Amgen, Bristol Myers Squibb (BMS); consultant services for Bayer, AstraZeneca, and Foundation Medicine; spouse is an employee and stockholder for Capio Biosciences all outside the submitted work. Michael Harrison reports grants from Merck, Genentech, AstraZeneca, Pfizer, BMS, and Janssen; personal feeds from Bayer, Genentech, AstraZeneca, Pfizer, BMS, and Janssen, all outside the submitted work. Daniel J. George reports grants from Janssen, Astellas/Pfizer, Dendreon, Bayer, Novartis, BMS, and Genentech/Roche; personal fees from Janssen, Astellas/Pfizer, Bayer, Merck, BMS, and Genetech/Roche; consulting services for Janssen, Astellas/Pfizer, Bayer, Merck, BMS, and Genentech/Roche, all outside the submitted work. Andrew J. Armstrong reports grants from Janssen, Astellas/Pfizer, Dendreon/San Power, Bayer, Novartis, Merck, BMS, Genetch/Roche, Active Biotech, Constellation, and AstraZenica; personal fees from Janssen, Astellas/Pfizer, Dendreon/San Power, Bayer, and Merck; consulting services for Janssen, Astellas/Pfizer, Dendreon/San Power, Bayer, Merck, and AstraZenica, all outside the submitted work. Matthew D. Tucker, Daniele Marin, Rajan T. Gupta, Santosh Gupta, William R. Berry, Sundhar Ramalingam, Yuan Wu, Patrick Healy, and Stacey Lisi collectively have no disclosures to report.

Figures

Figure 1
Figure 1
CONSORT diagram
Figure 2
Figure 2
Summation of tumor genomic mutations. Representation of all reported mutations present from all 18 men with available FoundationOne profiling. Four LRP1b mutations present: one loss, two missense mutations, and one frameshift mutation
Figure 3
Figure 3
Percent change in PSA over time on pembrolizumab. (A‐D) Spider plot showing percent change in total serum PSA levels over time (days) on treatment with pembrolizumab. (A) −100% to 1000 change. (B) −100% to 100% change. (C) Patient treated with combination enzalutamide and pembrolizumab highlighted in green. (D) Patients harboring LRP1b mutations heighted in yellow for ≥50% decrease in PSA and blue for ≥90% decrease in PSA. (E) Waterfall plot showing best percent reduction in total serum PSA. Asterisk indicates presence of LRP1b mutation
Figure 4
Figure 4
Radiograph showing partial response from patient 3. Representative CT scans of a patient with a partial imaging response (PR). CT scan 3 months out (right) shows substantially decreased size of bulky retroperitoneal lymphadenopathy. His PSA remained >90% below baseline and he remained on treatment at study end date, having received 11 cycles thus far
Figure 5
Figure 5
(A) LRP1b across all cancer types as per cBIOPORTAL. (B) LRP1b alterations present in prostate cancer as per cBIOPORTAL. (A) TCGA data from cBIOPORTAL showing prevalence of LRP1b mutations across tumor types; approximately 11% prevalence in prostate cancer. B) Prevalence of LRP1b mutations is from TCGA (yellow) approximately 11% (53/494), 11% MSKCC/DFCI (111/1013), and SU2C/PCF (red) 9% (14/150)26, 27, 28
See this image and copyright information in PMC

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