TY - JOUR
T1 - A phase 2 trial of avelumab in men with aggressive-variant or neuroendocrine prostate cancer
AU - Brown, Landon C.
AU - Halabi, Susan
AU - Somarelli, Jason A.
AU - Humeniuk, Michael
AU - Wu, Yuan
AU - Oyekunle, Taofik
AU - Howard, Lauren
AU - Huang, Jiaoti
AU - Anand, Monika
AU - Davies, Catrin
AU - Patel, Prekshaben
AU - Staats, Janet
AU - Weinhold, Kent J.
AU - Harrison, Michael R.
AU - Zhang, Tian
AU - George, Daniel J.
AU - Armstrong, Andrew J.
N1 - Funding Information:
AJA and JAS acknowledge funding support from NCI 1R01CA233585-03. The authors thank the patients and their families as well as the dedicated clinical and research staff at the Duke Cancer Institute. The authors acknowledge the efforts of Jennifer Enzor, Twan Weaver and the Duke Immune Profiling Core shared resource, and the Duke Cancer Institute biostatistics shared resource. This research was financially supported by Pfizer, as part of an alliance between Pfizer and Merck (CrossRef Funder ID:10.13039/100004755). Merck and Pfizer reviewed the manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors.
Funding Information:
AJA and JAS acknowledge funding support from NCI 1R01CA233585-03. The authors thank the patients and their families as well as the dedicated clinical and research staff at the Duke Cancer Institute. The authors acknowledge the efforts of Jennifer Enzor, Twan Weaver and the Duke Immune Profiling Core shared resource, and the Duke Cancer Institute biostatistics shared resource. This research was financially supported by Pfizer, as part of an alliance between Pfizer and Merck (CrossRef Funder ID:10.13039/100004755). Merck and Pfizer reviewed the manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/4
Y1 - 2022/4
N2 - Background: Men with progressive neuroendocrine or aggressive-variant metastatic prostate cancer (NEPC/AVPC) have a poor prognosis and limited treatment options, and immunotherapy has not been tested in such patients. Methods: We conducted an open label single center phase 2 trial (NCT03179410) of men with progressive NEPC/AVPC either defined by histology or AVPC criteria. Avelumab (10 mg/kg every 2 weeks) was administered until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Secondary endpoints included ORR, radiographic progression-free survival (rPFS), overall survival, and safety. Correlative studies included longitudinal peripheral blood immune phenotyping. The study was limited by the small number of patients enrolled and by the early termination due to COVID-19. Results: A total of 15 men with AVPC/NEPC were enrolled. The median age was 71 (range 51–85 years), and men had received a median of two prior therapies (range 1–3). Median PSA was 54 ng/dl (range 0–393), and 73% of men had liver metastasis. The ORR with avelumab in this setting by iRECIST or RECIST 1.1 was 6.7%, including one patient (6.7%) with a complete remission (CR), 20% with stable disease, and 67% with progressive disease. The patient with the CR had an MSH2 somatic mutation and MSI-high NEPC with central nervous system metastases, and his CR remains durable off all therapy for 2 years. The median rPFS was 1.8 months (95% CI 1.6–3.6 months), and median overall survival was 7.4 months (85% CI 2.8–12.6 months). Safety was consistent with the known profile of avelumab. Phenotyping of peripheral immune subsets suggest enhanced CXCR2-dependent myeloid and T-cell responses in this extraordinary responder. Conclusions: While the study was terminated early due to slow enrollment at the onset of the COVID-19 pandemic and lower than anticipated objective response rate, PD-L1 inhibition with avelumab monotherapy showed poor efficacy in patients with microsatellite stable NEPC/AVPC. Immune profiling revealed enhanced CXCR2 positive immune cell activation in the one extraordinary responder, suggesting potential mechanisms for further immunotherapy development in this population.
AB - Background: Men with progressive neuroendocrine or aggressive-variant metastatic prostate cancer (NEPC/AVPC) have a poor prognosis and limited treatment options, and immunotherapy has not been tested in such patients. Methods: We conducted an open label single center phase 2 trial (NCT03179410) of men with progressive NEPC/AVPC either defined by histology or AVPC criteria. Avelumab (10 mg/kg every 2 weeks) was administered until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Secondary endpoints included ORR, radiographic progression-free survival (rPFS), overall survival, and safety. Correlative studies included longitudinal peripheral blood immune phenotyping. The study was limited by the small number of patients enrolled and by the early termination due to COVID-19. Results: A total of 15 men with AVPC/NEPC were enrolled. The median age was 71 (range 51–85 years), and men had received a median of two prior therapies (range 1–3). Median PSA was 54 ng/dl (range 0–393), and 73% of men had liver metastasis. The ORR with avelumab in this setting by iRECIST or RECIST 1.1 was 6.7%, including one patient (6.7%) with a complete remission (CR), 20% with stable disease, and 67% with progressive disease. The patient with the CR had an MSH2 somatic mutation and MSI-high NEPC with central nervous system metastases, and his CR remains durable off all therapy for 2 years. The median rPFS was 1.8 months (95% CI 1.6–3.6 months), and median overall survival was 7.4 months (85% CI 2.8–12.6 months). Safety was consistent with the known profile of avelumab. Phenotyping of peripheral immune subsets suggest enhanced CXCR2-dependent myeloid and T-cell responses in this extraordinary responder. Conclusions: While the study was terminated early due to slow enrollment at the onset of the COVID-19 pandemic and lower than anticipated objective response rate, PD-L1 inhibition with avelumab monotherapy showed poor efficacy in patients with microsatellite stable NEPC/AVPC. Immune profiling revealed enhanced CXCR2 positive immune cell activation in the one extraordinary responder, suggesting potential mechanisms for further immunotherapy development in this population.
UR - http://www.scopus.com/inward/record.url?scp=85126315906&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85126315906&partnerID=8YFLogxK
U2 - 10.1038/s41391-022-00524-7
DO - 10.1038/s41391-022-00524-7
M3 - Article
C2 - 35292724
AN - SCOPUS:85126315906
SN - 1365-7852
VL - 25
SP - 762
EP - 769
JO - Prostate Cancer and Prostatic Diseases
JF - Prostate Cancer and Prostatic Diseases
IS - 4
ER -