A pilot trial of pembrolizumab plus prostatic cryotherapy for men with newly diagnosed oligometastatic hormone-sensitive prostate cancer

Ashley E Ross, Paula J Hurley, Phuoc T Tran, Steven P Rowe, Benjamin Benzon, Tanya O' Neal, Carolyn Chapman, Rana Harb, Yelena Milman, Bruce J Trock, Charles G Drake, Emmanuel S Antonarakis, Ashley E Ross, Paula J Hurley, Phuoc T Tran, Steven P Rowe, Benjamin Benzon, Tanya O' Neal, Carolyn Chapman, Rana Harb, Yelena Milman, Bruce J Trock, Charles G Drake, Emmanuel S Antonarakis

Abstract

Background: Monotherapy with immune checkpoint inhibitors has generally been unsuccessful in men with advanced prostate cancer. Preclinical data support the notion that cryotherapy may improve immune-mediated and anti-tumor responses. The objective of this study was to assess the safety and feasibility of whole-prostate gland cryotherapy combined with pembrolizumab and androgen deprivation in men with oligometastatic hormone-sensitive prostate cancer.

Methods: This single-institution, pilot trial recruited 12 patients with newly diagnosed oligometastatic prostate cancer between 2015 and 2016. Patients underwent whole-prostate cryoablation combined with short-term androgen deprivation (eight months) and pembrolizumab (6 doses). The primary clinical endpoints were the number of patients with a PSA level of <0.6 ng/mL at one year and the frequency of adverse events. Other outcome measures included progression-free survival and systemic therapy-free survival. Exploratory analyses included PD-L1 protein expression.

Results: Forty two percent (5/12) of patients had a PSAs of <0.6 ng/mL at one year though only 2 of these patients had recovered their testosterone at this time point. Median progression-free survival was 14 months, and median systemic therapy-free survival was 17.5 months. PD-L1 expression was not detectable by IHC in patients with evaluable tissue. All adverse events were grade ≤2, and there were no apparent complications from cryotherapy.

Conclusions: Whole-prostate cryoablation combined with short-term androgen deprivation and pembrolizumab treatment was well tolerated and no safety concerns were observed in men with oligometastatic prostate cancer. Though local disease appeared effectively treated in the majority of men, the regimen only infrequency led to sustained disease control following testosterone recovery.

Conflict of interest statement

Conflict of Interest

Ashley E. Ross has previously been a consultant for Healthtronics. Phuoc Tran has grant support from Astellas Pharm., RefleXion Medical, Inc and Bayer Healthcare; and has consulted for RefleXion Medical, Inc. Charles G. Drake acknowledges stock or ownership interests in Compugen, Harpoon, Kleo, Potenza, and Tizona Therapeutics, and has served as a consultant for Agenus, Dendreon, Janssen Oncology, Eli Lilly, Merck, AstraZeneca, MedImmune, Pierre Fabre, Genentech, and Genocea Biosciences. Emmanuel S. Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Medivation, AstraZeneca, Clovis, and Merck; he has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis, and Merck; and he is the co-inventor of an AR-V7 biomarker technology that has been licensed to Qiagen. No potential conflict of interests were disclosed by the other authors.

Figures

Fig. 1.
Fig. 1.
Outcomes in men with oligometastatic prostate cancer treated with whole prostate cryoablation in combination with androgen deprivation therapy and pembrolizumab. A, Waterfall plot of the best PSA response (percent fold change compared to baseline). B-D, Kaplan Meir survival analysis of (B) PSA progression-free, (C) systemic therapy-free, and (D) CRPC progression-free survival. E, Swimmers plots of PSA progression, new systemic therapy, CRPC, and death.
Fig. 2.
Fig. 2.
Representative IHC staining of CD4, CD8, and PD-L1 in prostate biopsy tissue.
Fig. 3.
Fig. 3.
Peripheral and tumor tissue TCR clonotype dynamics following cryotherapy, ADT and pembrolizumab. A, Histogram by patient of contracted and expanded T cell clones following the treatment regimen. PT9 is highlighted. B, T cell fraction at baseline and post-treatment (Post Tx) in tumor biopsy tissue from PT9 following 6 cycles of pembrolizumab. C, Simpson clonality from PT9 in both the blood and prostate tumor tissue Post Tx. Simpson clonality allows comparisons between blood and tissue samples that have large differences in number of productive templates. For reference, median Simpson clonality in healthy adults is 0.03. D, T cell clonotype frequencies from PT9 blood are plotted at baseline and Post-Tx with the rose and blue circles denoting expanded and contracted clones. Clones that also shared in the Post-Tx tumor tissue biopsy are outlined in black.

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