Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer

Mari Nakabayashi, Lilian Werner, Kevin D. Courtney, Geoffrey Buckle, William K. Oh, Glen J. Bubley, Julia H. Hayes, Douglas Weckstein, Aymen Elfiky, Danny M. Sims, Philip W. Kantoff, Mary Ellen Taplin

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Study Type - Therapy (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Despite expanding treatment options for castration-resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells' natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K-Akt pathway. Thus inhibition of AR signalling and PI3K-Akt-mTOR (a downstream mediator of the PI3K-Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K-Akt-mTOR. The AR pathway and the PI3K-Akt-mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K-Akt-mTOR inhibitors are in development and likely will be tested in combination in CRPC. OBJECTIVES To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration-resistant prostate cancer (CRPC). To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC. PATIENTS AND METHODS A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC. The primary endpoint was a composite of prostate-specific antigen (PSA) level and measurable disease response by standard criteria. This single-stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of ≥40% from a response rate of ≤20%, as expected for bicalutamide alone (α= 0.10, power = 0.90). RESULTS In total, 36 men were enrolled, with a median (range) age of 68 (60-72) years and median (range) baseline PSA level of 22.2 (8.4-121.3) ng/mL, and 89% had metastatic disease. There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months. There were two patients with a confirmed PSA level decline ≥50%. The median (interquartile range) time to progression was 8.7 (7.9-15.9) weeks. The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients. CONCLUSION The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.

Original languageEnglish (US)
Pages (from-to)1729-1735
Number of pages7
JournalBJU International
Volume110
Issue number11
DOIs
StatePublished - Dec 2012

Fingerprint

Castration
Prostatic Neoplasms
Phosphatidylinositol 3-Kinases
Androgen Receptors
Prostate-Specific Antigen
Everolimus
bicalutamide
Mucositis
Sirolimus
Sample Size
Appointments and Schedules
Therapeutics
Clinical Trials

Keywords

  • bicalutamide
  • castration-resistant prostate cancer
  • everolimus
  • mTOR
  • RAD001

ASJC Scopus subject areas

  • Urology

Cite this

Nakabayashi, M., Werner, L., Courtney, K. D., Buckle, G., Oh, W. K., Bubley, G. J., ... Taplin, M. E. (2012). Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer. BJU International, 110(11), 1729-1735. https://doi.org/10.1111/j.1464-410X.2012.11456.x

Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer. / Nakabayashi, Mari; Werner, Lilian; Courtney, Kevin D.; Buckle, Geoffrey; Oh, William K.; Bubley, Glen J.; Hayes, Julia H.; Weckstein, Douglas; Elfiky, Aymen; Sims, Danny M.; Kantoff, Philip W.; Taplin, Mary Ellen.

In: BJU International, Vol. 110, No. 11, 12.2012, p. 1729-1735.

Research output: Contribution to journalArticle

Nakabayashi, M, Werner, L, Courtney, KD, Buckle, G, Oh, WK, Bubley, GJ, Hayes, JH, Weckstein, D, Elfiky, A, Sims, DM, Kantoff, PW & Taplin, ME 2012, 'Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer', BJU International, vol. 110, no. 11, pp. 1729-1735. https://doi.org/10.1111/j.1464-410X.2012.11456.x
Nakabayashi, Mari ; Werner, Lilian ; Courtney, Kevin D. ; Buckle, Geoffrey ; Oh, William K. ; Bubley, Glen J. ; Hayes, Julia H. ; Weckstein, Douglas ; Elfiky, Aymen ; Sims, Danny M. ; Kantoff, Philip W. ; Taplin, Mary Ellen. / Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer. In: BJU International. 2012 ; Vol. 110, No. 11. pp. 1729-1735.
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abstract = "Study Type - Therapy (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Despite expanding treatment options for castration-resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells' natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K-Akt pathway. Thus inhibition of AR signalling and PI3K-Akt-mTOR (a downstream mediator of the PI3K-Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K-Akt-mTOR. The AR pathway and the PI3K-Akt-mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K-Akt-mTOR inhibitors are in development and likely will be tested in combination in CRPC. OBJECTIVES To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration-resistant prostate cancer (CRPC). To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC. PATIENTS AND METHODS A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC. The primary endpoint was a composite of prostate-specific antigen (PSA) level and measurable disease response by standard criteria. This single-stage trial with a sample size of 38 eligible patients provided 90{\%} power to differentiate a response rate of ≥40{\%} from a response rate of ≤20{\%}, as expected for bicalutamide alone (α= 0.10, power = 0.90). RESULTS In total, 36 men were enrolled, with a median (range) age of 68 (60-72) years and median (range) baseline PSA level of 22.2 (8.4-121.3) ng/mL, and 89{\%} had metastatic disease. There were 31 (86{\%}) patients had previously used bicalutamide for a median duration of 7.4 months. There were two patients with a confirmed PSA level decline ≥50{\%}. The median (interquartile range) time to progression was 8.7 (7.9-15.9) weeks. The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56{\%}) patients. CONCLUSION The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.",
keywords = "bicalutamide, castration-resistant prostate cancer, everolimus, mTOR, RAD001",
author = "Mari Nakabayashi and Lilian Werner and Courtney, {Kevin D.} and Geoffrey Buckle and Oh, {William K.} and Bubley, {Glen J.} and Hayes, {Julia H.} and Douglas Weckstein and Aymen Elfiky and Sims, {Danny M.} and Kantoff, {Philip W.} and Taplin, {Mary Ellen}",
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TY - JOUR

T1 - Phase II trial of RAD001 and bicalutamide for castration-resistant prostate cancer

AU - Nakabayashi, Mari

AU - Werner, Lilian

AU - Courtney, Kevin D.

AU - Buckle, Geoffrey

AU - Oh, William K.

AU - Bubley, Glen J.

AU - Hayes, Julia H.

AU - Weckstein, Douglas

AU - Elfiky, Aymen

AU - Sims, Danny M.

AU - Kantoff, Philip W.

AU - Taplin, Mary Ellen

PY - 2012/12

Y1 - 2012/12

N2 - Study Type - Therapy (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Despite expanding treatment options for castration-resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells' natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K-Akt pathway. Thus inhibition of AR signalling and PI3K-Akt-mTOR (a downstream mediator of the PI3K-Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K-Akt-mTOR. The AR pathway and the PI3K-Akt-mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K-Akt-mTOR inhibitors are in development and likely will be tested in combination in CRPC. OBJECTIVES To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration-resistant prostate cancer (CRPC). To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC. PATIENTS AND METHODS A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC. The primary endpoint was a composite of prostate-specific antigen (PSA) level and measurable disease response by standard criteria. This single-stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of ≥40% from a response rate of ≤20%, as expected for bicalutamide alone (α= 0.10, power = 0.90). RESULTS In total, 36 men were enrolled, with a median (range) age of 68 (60-72) years and median (range) baseline PSA level of 22.2 (8.4-121.3) ng/mL, and 89% had metastatic disease. There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months. There were two patients with a confirmed PSA level decline ≥50%. The median (interquartile range) time to progression was 8.7 (7.9-15.9) weeks. The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients. CONCLUSION The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.

AB - Study Type - Therapy (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Despite expanding treatment options for castration-resistant prostate cancer (CRPC), therapies with long response duration remain intangible due to prostate cancer cells' natural ability to develop iterative resistance. Androgen receptor (AR) signaling has been shown to play a critical role in CRPC and its expression is regulated by the PI3K-Akt pathway. Thus inhibition of AR signalling and PI3K-Akt-mTOR (a downstream mediator of the PI3K-Akt pathway) pathway is a logical combination in CRPC and we report a phase II trial of RAD001 and bicalutamide. Our study is the first clinical trial report of an AR inhibitor of PI3K-Akt-mTOR. The AR pathway and the PI3K-Akt-mTOR pathway are two of the most relevant growth pathway for CRPC. Despite low efficacy results from our trial there will be significant interest in the field for these data (dose, schedule, response, toxicity, trial design) as newer generations of both AR inhibitors and PI3K-Akt-mTOR inhibitors are in development and likely will be tested in combination in CRPC. OBJECTIVES To determine best overall response and duration of response of RAD001, a selective inhibitor of mammalian target of rapamycin, in combination with bicalutamide in castration-resistant prostate cancer (CRPC). To characterize the toxicity profile of RAD001 in combination with bicalutamide in patients with CRPC. PATIENTS AND METHODS A phase II study was conducted to explore the efficacy and tolerability of RAD001 (10 mg daily) in combination with bicalutamide (50 mg daily) in men with progressive CRPC. The primary endpoint was a composite of prostate-specific antigen (PSA) level and measurable disease response by standard criteria. This single-stage trial with a sample size of 38 eligible patients provided 90% power to differentiate a response rate of ≥40% from a response rate of ≤20%, as expected for bicalutamide alone (α= 0.10, power = 0.90). RESULTS In total, 36 men were enrolled, with a median (range) age of 68 (60-72) years and median (range) baseline PSA level of 22.2 (8.4-121.3) ng/mL, and 89% had metastatic disease. There were 31 (86%) patients had previously used bicalutamide for a median duration of 7.4 months. There were two patients with a confirmed PSA level decline ≥50%. The median (interquartile range) time to progression was 8.7 (7.9-15.9) weeks. The most common toxicity was grade 1/2 mucositis, which was observed in 20 (56%) patients. CONCLUSION The combination of RAD001 and bicalutamide in men with CRPC was well tolerated but had low activity and failed to achieve the primary endpoint of improved response compared to the results previously achieved for bicalutamide alone in this population.

KW - bicalutamide

KW - castration-resistant prostate cancer

KW - everolimus

KW - mTOR

KW - RAD001

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