Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial

Eugene Shenderov; Karim Boudadi; Wei Fu; Hao Wang; Rana Sullivan; Alice Jordan; Donna Dowling; Rana Harb; Joseph Schonhoft; Adam Jendrisak; Michael A. Carducci; Mario A. Eisenberger; James R. Eshleman; Jun Luo; Charles G. Drake; Drew M. Pardoll; Emmanuel S. Antonarakis

doi:10.1002/pros.24110

Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial

Eugene Shenderov, Karim Boudadi, Wei Fu, Hao Wang, Rana Sullivan, Alice Jordan, Donna Dowling, Rana Harb, Joseph Schonhoft, Adam Jendrisak, Michael A. Carducci, Mario A. Eisenberger, James R. Eshleman, Jun Luo, Charles G. Drake, Drew M. Pardoll, Emmanuel S. Antonarakis

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

Background: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival. Methods: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7–expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-to-clinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS). Results: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%) in Cohort 1 and 0/9 in Cohort 2 in those with measureable disease, median PSA-PFS was 3.0 (95% confidence interval [CI]: 2.1–NR) in cohort 1 and 2.7 (95% CI: 2.1–5.9) months in cohort 2, and median PFS was 3.7 (95% CI: 2.8–7.5) in cohort 1 and 2.9 (95% CI: 1.3–5.8) months in cohort 2. Three of 15 patients in cohort 1 (20%, 95% CI: 7.1%–45.2%) and 4/15 patients (26.7%, 95% CI: 10.5%–52.4%) in cohort 2 achieved a durable PFS lasting greater than 24 weeks. Median OS was 8.2 (95% CI: 5.5–10.4) in cohort 1 and 14.2 (95% CI: 8.5–NA) months in cohort 2. Efficacy results were not statistically different between cohorts. Grade-3/4 adverse events occurred in 7/15 cohort 1 patients (46%) and 8/15 cohort 2 patients (53%). Combined cohort (N = 30) baseline alkaline phosphatase and cytokine analysis suggested improved OS for patients with lower alkaline phosphatase (hazards ratio [HR], 0.30; 95% CI: 0.11–0.82), lower circulating interleukin-7 (IL-7) (HR, 0.24; 95% Cl: 0.06–0.93) and IL-6 (HR, 0.13; 95% Cl: 0.03–0.52) levels, and higher circulating IL-17 (HR, 4.53; 95% CI: 1.47–13.93) levels. There was a trend towards improved outcomes in men with low sPD-L1 serum levels. Conclusion: Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, −7, and −17) may be prognostic for outcomes to immunotherapy.

Original language	English (US)
Pages (from-to)	326-338
Number of pages	13
Journal	Prostate
Volume	81
Issue number	6
DOIs	https://doi.org/10.1002/pros.24110
State	Published - May 2021
Externally published	Yes

Bibliographical note

Funding Information:
The authors would like to thank all patients, families, and caregivers who participated in this study. This trial is registered at ClinicalTrials. gov (NCT02601014). This investigator initiated research was sponsored by Bristol-Myers Squibb (BMS, Princeton, NJ) who also provided both study drugs free of cost. This study was also partially supported by National Institutes of Health Cancer Center Support Grant P30 CA006973 (ES, ESA), Prostate Cancer Foundation Young Investigator Award (ES), Department of Defense grant W81XWH-16-PCRP-CCRSA (ESA) and grant W81XWH-19-1-0511 (ES), and the Bloomberg-Kimmel Institute for Cancer Immunotherapy (ES, DMP, ESA).

Publisher Copyright:
© 2021 Wiley Periodicals LLC

Keywords

enzalutamide
immunotherapy
ipilimumab
nivolumab
prognostic biomarker
prostatic cancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/pros.24110

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Shenderov, E., Boudadi, K., Fu, W., Wang, H., Sullivan, R., Jordan, A., Dowling, D., Harb, R., Schonhoft, J., Jendrisak, A., Carducci, M. A., Eisenberger, M. A., Eshleman, J. R., Luo, J., Drake, C. G., Pardoll, D. M., & Antonarakis, E. S. (2021). Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial. Prostate, 81(6), 326-338. https://doi.org/10.1002/pros.24110

Shenderov, E, Boudadi, K, Fu, W, Wang, H, Sullivan, R, Jordan, A, Dowling, D, Harb, R, Schonhoft, J, Jendrisak, A, Carducci, MA, Eisenberger, MA, Eshleman, JR, Luo, J, Drake, CG, Pardoll, DM & Antonarakis, ES 2021, 'Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial', Prostate, vol. 81, no. 6, pp. 326-338. https://doi.org/10.1002/pros.24110

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title = "Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial",

abstract = "Background: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival. Methods: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7–expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-to-clinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS). Results: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%) in Cohort 1 and 0/9 in Cohort 2 in those with measureable disease, median PSA-PFS was 3.0 (95% confidence interval [CI]: 2.1–NR) in cohort 1 and 2.7 (95% CI: 2.1–5.9) months in cohort 2, and median PFS was 3.7 (95% CI: 2.8–7.5) in cohort 1 and 2.9 (95% CI: 1.3–5.8) months in cohort 2. Three of 15 patients in cohort 1 (20%, 95% CI: 7.1%–45.2%) and 4/15 patients (26.7%, 95% CI: 10.5%–52.4%) in cohort 2 achieved a durable PFS lasting greater than 24 weeks. Median OS was 8.2 (95% CI: 5.5–10.4) in cohort 1 and 14.2 (95% CI: 8.5–NA) months in cohort 2. Efficacy results were not statistically different between cohorts. Grade-3/4 adverse events occurred in 7/15 cohort 1 patients (46%) and 8/15 cohort 2 patients (53%). Combined cohort (N = 30) baseline alkaline phosphatase and cytokine analysis suggested improved OS for patients with lower alkaline phosphatase (hazards ratio [HR], 0.30; 95% CI: 0.11–0.82), lower circulating interleukin-7 (IL-7) (HR, 0.24; 95% Cl: 0.06–0.93) and IL-6 (HR, 0.13; 95% Cl: 0.03–0.52) levels, and higher circulating IL-17 (HR, 4.53; 95% CI: 1.47–13.93) levels. There was a trend towards improved outcomes in men with low sPD-L1 serum levels. Conclusion: Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, −7, and −17) may be prognostic for outcomes to immunotherapy.",

keywords = "enzalutamide, immunotherapy, ipilimumab, nivolumab, prognostic biomarker, prostatic cancer",

author = "Eugene Shenderov and Karim Boudadi and Wei Fu and Hao Wang and Rana Sullivan and Alice Jordan and Donna Dowling and Rana Harb and Joseph Schonhoft and Adam Jendrisak and Carducci, {Michael A.} and Eisenberger, {Mario A.} and Eshleman, {James R.} and Jun Luo and Drake, {Charles G.} and Pardoll, {Drew M.} and Antonarakis, {Emmanuel S.}",

note = "Funding Information: The authors would like to thank all patients, families, and caregivers who participated in this study. This trial is registered at ClinicalTrials. gov (NCT02601014). This investigator initiated research was sponsored by Bristol-Myers Squibb (BMS, Princeton, NJ) who also provided both study drugs free of cost. This study was also partially supported by National Institutes of Health Cancer Center Support Grant P30 CA006973 (ES, ESA), Prostate Cancer Foundation Young Investigator Award (ES), Department of Defense grant W81XWH-16-PCRP-CCRSA (ESA) and grant W81XWH-19-1-0511 (ES), and the Bloomberg-Kimmel Institute for Cancer Immunotherapy (ES, DMP, ESA). Publisher Copyright: {\textcopyright} 2021 Wiley Periodicals LLC",

year = "2021",

month = may,

doi = "10.1002/pros.24110",

language = "English (US)",

volume = "81",

pages = "326--338",

journal = "Prostate",

issn = "0270-4137",

publisher = "John Wiley and Sons Inc.",

number = "6",

}

TY - JOUR

T1 - Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer

T2 - A phase-2 nonrandomized clinical trial

AU - Shenderov, Eugene

AU - Boudadi, Karim

AU - Fu, Wei

AU - Wang, Hao

AU - Sullivan, Rana

AU - Jordan, Alice

AU - Dowling, Donna

AU - Harb, Rana

AU - Schonhoft, Joseph

AU - Jendrisak, Adam

AU - Carducci, Michael A.

AU - Eisenberger, Mario A.

AU - Eshleman, James R.

AU - Luo, Jun

AU - Drake, Charles G.

AU - Pardoll, Drew M.

AU - Antonarakis, Emmanuel S.

N1 - Funding Information: The authors would like to thank all patients, families, and caregivers who participated in this study. This trial is registered at ClinicalTrials. gov (NCT02601014). This investigator initiated research was sponsored by Bristol-Myers Squibb (BMS, Princeton, NJ) who also provided both study drugs free of cost. This study was also partially supported by National Institutes of Health Cancer Center Support Grant P30 CA006973 (ES, ESA), Prostate Cancer Foundation Young Investigator Award (ES), Department of Defense grant W81XWH-16-PCRP-CCRSA (ESA) and grant W81XWH-19-1-0511 (ES), and the Bloomberg-Kimmel Institute for Cancer Immunotherapy (ES, DMP, ESA). Publisher Copyright: © 2021 Wiley Periodicals LLC

PY - 2021/5

Y1 - 2021/5

N2 - Background: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival. Methods: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7–expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-to-clinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS). Results: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%) in Cohort 1 and 0/9 in Cohort 2 in those with measureable disease, median PSA-PFS was 3.0 (95% confidence interval [CI]: 2.1–NR) in cohort 1 and 2.7 (95% CI: 2.1–5.9) months in cohort 2, and median PFS was 3.7 (95% CI: 2.8–7.5) in cohort 1 and 2.9 (95% CI: 1.3–5.8) months in cohort 2. Three of 15 patients in cohort 1 (20%, 95% CI: 7.1%–45.2%) and 4/15 patients (26.7%, 95% CI: 10.5%–52.4%) in cohort 2 achieved a durable PFS lasting greater than 24 weeks. Median OS was 8.2 (95% CI: 5.5–10.4) in cohort 1 and 14.2 (95% CI: 8.5–NA) months in cohort 2. Efficacy results were not statistically different between cohorts. Grade-3/4 adverse events occurred in 7/15 cohort 1 patients (46%) and 8/15 cohort 2 patients (53%). Combined cohort (N = 30) baseline alkaline phosphatase and cytokine analysis suggested improved OS for patients with lower alkaline phosphatase (hazards ratio [HR], 0.30; 95% CI: 0.11–0.82), lower circulating interleukin-7 (IL-7) (HR, 0.24; 95% Cl: 0.06–0.93) and IL-6 (HR, 0.13; 95% Cl: 0.03–0.52) levels, and higher circulating IL-17 (HR, 4.53; 95% CI: 1.47–13.93) levels. There was a trend towards improved outcomes in men with low sPD-L1 serum levels. Conclusion: Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, −7, and −17) may be prognostic for outcomes to immunotherapy.

AB - Background: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival. Methods: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7–expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-to-clinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS). Results: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%) in Cohort 1 and 0/9 in Cohort 2 in those with measureable disease, median PSA-PFS was 3.0 (95% confidence interval [CI]: 2.1–NR) in cohort 1 and 2.7 (95% CI: 2.1–5.9) months in cohort 2, and median PFS was 3.7 (95% CI: 2.8–7.5) in cohort 1 and 2.9 (95% CI: 1.3–5.8) months in cohort 2. Three of 15 patients in cohort 1 (20%, 95% CI: 7.1%–45.2%) and 4/15 patients (26.7%, 95% CI: 10.5%–52.4%) in cohort 2 achieved a durable PFS lasting greater than 24 weeks. Median OS was 8.2 (95% CI: 5.5–10.4) in cohort 1 and 14.2 (95% CI: 8.5–NA) months in cohort 2. Efficacy results were not statistically different between cohorts. Grade-3/4 adverse events occurred in 7/15 cohort 1 patients (46%) and 8/15 cohort 2 patients (53%). Combined cohort (N = 30) baseline alkaline phosphatase and cytokine analysis suggested improved OS for patients with lower alkaline phosphatase (hazards ratio [HR], 0.30; 95% CI: 0.11–0.82), lower circulating interleukin-7 (IL-7) (HR, 0.24; 95% Cl: 0.06–0.93) and IL-6 (HR, 0.13; 95% Cl: 0.03–0.52) levels, and higher circulating IL-17 (HR, 4.53; 95% CI: 1.47–13.93) levels. There was a trend towards improved outcomes in men with low sPD-L1 serum levels. Conclusion: Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, −7, and −17) may be prognostic for outcomes to immunotherapy.

KW - enzalutamide

KW - immunotherapy

KW - ipilimumab

KW - nivolumab

KW - prognostic biomarker

KW - prostatic cancer

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UR - http://www.scopus.com/inward/citedby.url?scp=85101751191&partnerID=8YFLogxK

U2 - 10.1002/pros.24110

DO - 10.1002/pros.24110

M3 - Article

C2 - 33636027

AN - SCOPUS:85101751191

SN - 0270-4137

VL - 81

SP - 326

EP - 338

JO - Prostate

JF - Prostate

IS - 6

ER -

Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial

Abstract

Bibliographical note

Keywords

UN SDGs

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