PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open-label single-arm phase 2 study

Daniel P. Petrylak, Nicholas J. Vogelzang, Kamal Chatta, Mark T. Fleming, David C. Smith, Leonard J. Appleman, Arif Hussain, Manuel Modiano, Parminder Singh, Scott T. Tagawa, Ira Gore, Edward F. McClay, Anthony E. Mega, A. Oliver Sartor, Bradley Somer, Raymond Wadlow, Neal D. Shore, William C. Olson, Nancy Stambler, Vincent A. DiPippoRobert J. Israel

Research output: Contribution to journalArticle

Abstract

Background: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. Methods: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. Results: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. Conclusions: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.

Original languageEnglish (US)
JournalProstate
DOIs
StateAccepted/In press - Jan 1 2019

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Castration
Circulating Neoplastic Cells
Prostatic Neoplasms
Safety
Prostate-Specific Antigen
Drug Therapy
Neutropenia
Biomarkers
MDV 3100
human glutamate carboxypeptidase II
abiraterone
Therapeutics
Febrile Neutropenia
Hyponatremia
Constipation
Dehydration
Terminology
Electrolytes
Fatigue
Immunoglobulins

Keywords

  • antibody-drug conjugate
  • mCRPC
  • prostate-specific membrane antigen

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide : Efficacy and safety in open-label single-arm phase 2 study. / Petrylak, Daniel P.; Vogelzang, Nicholas J.; Chatta, Kamal; Fleming, Mark T.; Smith, David C.; Appleman, Leonard J.; Hussain, Arif; Modiano, Manuel; Singh, Parminder; Tagawa, Scott T.; Gore, Ira; McClay, Edward F.; Mega, Anthony E.; Sartor, A. Oliver; Somer, Bradley; Wadlow, Raymond; Shore, Neal D.; Olson, William C.; Stambler, Nancy; DiPippo, Vincent A.; Israel, Robert J.

In: Prostate, 01.01.2019.

Research output: Contribution to journalArticle

Petrylak, DP, Vogelzang, NJ, Chatta, K, Fleming, MT, Smith, DC, Appleman, LJ, Hussain, A, Modiano, M, Singh, P, Tagawa, ST, Gore, I, McClay, EF, Mega, AE, Sartor, AO, Somer, B, Wadlow, R, Shore, ND, Olson, WC, Stambler, N, DiPippo, VA & Israel, RJ 2019, 'PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open-label single-arm phase 2 study', Prostate. https://doi.org/10.1002/pros.23922
Petrylak, Daniel P. ; Vogelzang, Nicholas J. ; Chatta, Kamal ; Fleming, Mark T. ; Smith, David C. ; Appleman, Leonard J. ; Hussain, Arif ; Modiano, Manuel ; Singh, Parminder ; Tagawa, Scott T. ; Gore, Ira ; McClay, Edward F. ; Mega, Anthony E. ; Sartor, A. Oliver ; Somer, Bradley ; Wadlow, Raymond ; Shore, Neal D. ; Olson, William C. ; Stambler, Nancy ; DiPippo, Vincent A. ; Israel, Robert J. / PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide : Efficacy and safety in open-label single-arm phase 2 study. In: Prostate. 2019.
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abstract = "Background: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. Methods: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-na{\"i}ve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. Results: PSA declines ≥50{\%} occurred in 14{\%} of all treated (n = 113) and 21{\%} of chemotherapy-na{\"i}ve subjects (n = 34). CTC declines ≥50{\%} were seen in 78{\%} of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89{\%} of chemotherapy-na{\"i}ve subjects (n = 19); 47{\%} of all treated and 53{\%} of chemotherapy-na{\"i}ve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7{\%}) subjects; 5.7{\%} of subjects in the chemotherapy-na{\"i}ve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. Conclusions: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.",
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year = "2019",
month = "1",
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doi = "10.1002/pros.23922",
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journal = "Prostate",
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TY - JOUR

T1 - PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide

T2 - Efficacy and safety in open-label single-arm phase 2 study

AU - Petrylak, Daniel P.

AU - Vogelzang, Nicholas J.

AU - Chatta, Kamal

AU - Fleming, Mark T.

AU - Smith, David C.

AU - Appleman, Leonard J.

AU - Hussain, Arif

AU - Modiano, Manuel

AU - Singh, Parminder

AU - Tagawa, Scott T.

AU - Gore, Ira

AU - McClay, Edward F.

AU - Mega, Anthony E.

AU - Sartor, A. Oliver

AU - Somer, Bradley

AU - Wadlow, Raymond

AU - Shore, Neal D.

AU - Olson, William C.

AU - Stambler, Nancy

AU - DiPippo, Vincent A.

AU - Israel, Robert J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. Methods: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. Results: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. Conclusions: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.

AB - Background: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. Methods: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. Results: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. Conclusions: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.

KW - antibody-drug conjugate

KW - mCRPC

KW - prostate-specific membrane antigen

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