Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer

Andrew J. Armstrong, Susan Halabi, Patrick Healy, Joshi Alumkal, Carolyn Winters, Julie Kephart, Rhonda L. Bitting, Carey Hobbs, Colleen F. Soleau, Tomasz (Tom) Beer, Rachel Slottke, Kelly Mundy, Evan Y. Yu, Daniel J. George

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    Abstract

    Background Phosphatidylinositol-3-kinase (PI3K) and androgen receptor pathway activation is common in metastatic castration resistant prostate cancer (mCRPC). Buparlisib is an oral, pan-class I PI3 kinase inhibitor. Methods This was a multisite single arm phase II trial of buparlisib 100 mg ± enzalutamide daily in men with mCRPC whose disease progressed on or who were not candidates for docetaxel. The primary end-point was the rate of radiographic/clinical progression-free survival (PFS) at 6 months. Results Thirty men were accrued: 67% post-docetaxel; median prostate specific antigen (PSA) was 70 ng/dl, 83% had ≥4 prior therapies for mCRPC; 43% received concurrent enzalutamide. The final 6 month PFS rate was estimated to be 10% (95% confidence interval 2.5–23.6%). Median PFS was 1.9 months and was 3.5 months with concurrent enzalutamide. Median overall survival was 10.6 months. Concurrent enzalutamide led to a five-fold reduction in buparlisib concentrations. PSA declines were observed in 23%; no patients achieved a ≥50% decline, and no radiographic responses were observed. Severe adverse events occurred in four men including respiratory infection and multi-organ failure, urinary tract obstruction, confusion and one seizure in the setting of a new central nervous system (CNS) metastasis. Grade III adverse events were seen in 43% of patients; common toxicities included grade I–II weight loss, diarrhoea, nausea, fatigue, anorexia, rash, hyperglycemia and anxiety/mood disorders. Conclusions Buparlisib did not demonstrate significant activity in men with mCRPC, suggesting that PI3K inhibition is not sufficient to reverse resistant mCRPC progression. Future studies of PI3K pathway inhibitors with concurrent enzalutamide should develop optimal dosing and focus on selected patients more likely to benefit.

    Original languageEnglish (US)
    Pages (from-to)228-236
    Number of pages9
    JournalEuropean Journal of Cancer
    Volume81
    DOIs
    StatePublished - Aug 1 2017

    Fingerprint

    Castration
    Phosphatidylinositol 3-Kinases
    docetaxel
    Phosphatidylinositol 3-Kinase
    Prostatic Neoplasms
    Disease-Free Survival
    Prostate-Specific Antigen
    Confusion
    Androgen Receptors
    Anorexia
    Exanthema
    Anxiety Disorders
    Urinary Tract
    Mood Disorders
    Respiratory Tract Infections
    Hyperglycemia
    Nausea
    Fatigue
    Weight Loss
    Diarrhea

    Keywords

    • BKM-120
    • Buparlisib
    • Clinical trial
    • Enzalutamide
    • Metastatic castration resistant prostate cancer
    • PI3 kinase
    • Prostate cancer

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer. / Armstrong, Andrew J.; Halabi, Susan; Healy, Patrick; Alumkal, Joshi; Winters, Carolyn; Kephart, Julie; Bitting, Rhonda L.; Hobbs, Carey; Soleau, Colleen F.; Beer, Tomasz (Tom); Slottke, Rachel; Mundy, Kelly; Yu, Evan Y.; George, Daniel J.

    In: European Journal of Cancer, Vol. 81, 01.08.2017, p. 228-236.

    Research output: Contribution to journalArticle

    Armstrong, AJ, Halabi, S, Healy, P, Alumkal, J, Winters, C, Kephart, J, Bitting, RL, Hobbs, C, Soleau, CF, Beer, TT, Slottke, R, Mundy, K, Yu, EY & George, DJ 2017, 'Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer', European Journal of Cancer, vol. 81, pp. 228-236. https://doi.org/10.1016/j.ejca.2017.02.030
    Armstrong, Andrew J. ; Halabi, Susan ; Healy, Patrick ; Alumkal, Joshi ; Winters, Carolyn ; Kephart, Julie ; Bitting, Rhonda L. ; Hobbs, Carey ; Soleau, Colleen F. ; Beer, Tomasz (Tom) ; Slottke, Rachel ; Mundy, Kelly ; Yu, Evan Y. ; George, Daniel J. / Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer. In: European Journal of Cancer. 2017 ; Vol. 81. pp. 228-236.
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    abstract = "Background Phosphatidylinositol-3-kinase (PI3K) and androgen receptor pathway activation is common in metastatic castration resistant prostate cancer (mCRPC). Buparlisib is an oral, pan-class I PI3 kinase inhibitor. Methods This was a multisite single arm phase II trial of buparlisib 100 mg ± enzalutamide daily in men with mCRPC whose disease progressed on or who were not candidates for docetaxel. The primary end-point was the rate of radiographic/clinical progression-free survival (PFS) at 6 months. Results Thirty men were accrued: 67{\%} post-docetaxel; median prostate specific antigen (PSA) was 70 ng/dl, 83{\%} had ≥4 prior therapies for mCRPC; 43{\%} received concurrent enzalutamide. The final 6 month PFS rate was estimated to be 10{\%} (95{\%} confidence interval 2.5–23.6{\%}). Median PFS was 1.9 months and was 3.5 months with concurrent enzalutamide. Median overall survival was 10.6 months. Concurrent enzalutamide led to a five-fold reduction in buparlisib concentrations. PSA declines were observed in 23{\%}; no patients achieved a ≥50{\%} decline, and no radiographic responses were observed. Severe adverse events occurred in four men including respiratory infection and multi-organ failure, urinary tract obstruction, confusion and one seizure in the setting of a new central nervous system (CNS) metastasis. Grade III adverse events were seen in 43{\%} of patients; common toxicities included grade I–II weight loss, diarrhoea, nausea, fatigue, anorexia, rash, hyperglycemia and anxiety/mood disorders. Conclusions Buparlisib did not demonstrate significant activity in men with mCRPC, suggesting that PI3K inhibition is not sufficient to reverse resistant mCRPC progression. Future studies of PI3K pathway inhibitors with concurrent enzalutamide should develop optimal dosing and focus on selected patients more likely to benefit.",
    keywords = "BKM-120, Buparlisib, Clinical trial, Enzalutamide, Metastatic castration resistant prostate cancer, PI3 kinase, Prostate cancer",
    author = "Armstrong, {Andrew J.} and Susan Halabi and Patrick Healy and Joshi Alumkal and Carolyn Winters and Julie Kephart and Bitting, {Rhonda L.} and Carey Hobbs and Soleau, {Colleen F.} and Beer, {Tomasz (Tom)} and Rachel Slottke and Kelly Mundy and Yu, {Evan Y.} and George, {Daniel J.}",
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    T1 - Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer

    AU - Armstrong, Andrew J.

    AU - Halabi, Susan

    AU - Healy, Patrick

    AU - Alumkal, Joshi

    AU - Winters, Carolyn

    AU - Kephart, Julie

    AU - Bitting, Rhonda L.

    AU - Hobbs, Carey

    AU - Soleau, Colleen F.

    AU - Beer, Tomasz (Tom)

    AU - Slottke, Rachel

    AU - Mundy, Kelly

    AU - Yu, Evan Y.

    AU - George, Daniel J.

    PY - 2017/8/1

    Y1 - 2017/8/1

    N2 - Background Phosphatidylinositol-3-kinase (PI3K) and androgen receptor pathway activation is common in metastatic castration resistant prostate cancer (mCRPC). Buparlisib is an oral, pan-class I PI3 kinase inhibitor. Methods This was a multisite single arm phase II trial of buparlisib 100 mg ± enzalutamide daily in men with mCRPC whose disease progressed on or who were not candidates for docetaxel. The primary end-point was the rate of radiographic/clinical progression-free survival (PFS) at 6 months. Results Thirty men were accrued: 67% post-docetaxel; median prostate specific antigen (PSA) was 70 ng/dl, 83% had ≥4 prior therapies for mCRPC; 43% received concurrent enzalutamide. The final 6 month PFS rate was estimated to be 10% (95% confidence interval 2.5–23.6%). Median PFS was 1.9 months and was 3.5 months with concurrent enzalutamide. Median overall survival was 10.6 months. Concurrent enzalutamide led to a five-fold reduction in buparlisib concentrations. PSA declines were observed in 23%; no patients achieved a ≥50% decline, and no radiographic responses were observed. Severe adverse events occurred in four men including respiratory infection and multi-organ failure, urinary tract obstruction, confusion and one seizure in the setting of a new central nervous system (CNS) metastasis. Grade III adverse events were seen in 43% of patients; common toxicities included grade I–II weight loss, diarrhoea, nausea, fatigue, anorexia, rash, hyperglycemia and anxiety/mood disorders. Conclusions Buparlisib did not demonstrate significant activity in men with mCRPC, suggesting that PI3K inhibition is not sufficient to reverse resistant mCRPC progression. Future studies of PI3K pathway inhibitors with concurrent enzalutamide should develop optimal dosing and focus on selected patients more likely to benefit.

    AB - Background Phosphatidylinositol-3-kinase (PI3K) and androgen receptor pathway activation is common in metastatic castration resistant prostate cancer (mCRPC). Buparlisib is an oral, pan-class I PI3 kinase inhibitor. Methods This was a multisite single arm phase II trial of buparlisib 100 mg ± enzalutamide daily in men with mCRPC whose disease progressed on or who were not candidates for docetaxel. The primary end-point was the rate of radiographic/clinical progression-free survival (PFS) at 6 months. Results Thirty men were accrued: 67% post-docetaxel; median prostate specific antigen (PSA) was 70 ng/dl, 83% had ≥4 prior therapies for mCRPC; 43% received concurrent enzalutamide. The final 6 month PFS rate was estimated to be 10% (95% confidence interval 2.5–23.6%). Median PFS was 1.9 months and was 3.5 months with concurrent enzalutamide. Median overall survival was 10.6 months. Concurrent enzalutamide led to a five-fold reduction in buparlisib concentrations. PSA declines were observed in 23%; no patients achieved a ≥50% decline, and no radiographic responses were observed. Severe adverse events occurred in four men including respiratory infection and multi-organ failure, urinary tract obstruction, confusion and one seizure in the setting of a new central nervous system (CNS) metastasis. Grade III adverse events were seen in 43% of patients; common toxicities included grade I–II weight loss, diarrhoea, nausea, fatigue, anorexia, rash, hyperglycemia and anxiety/mood disorders. Conclusions Buparlisib did not demonstrate significant activity in men with mCRPC, suggesting that PI3K inhibition is not sufficient to reverse resistant mCRPC progression. Future studies of PI3K pathway inhibitors with concurrent enzalutamide should develop optimal dosing and focus on selected patients more likely to benefit.

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    KW - Prostate cancer

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