Reference Detail

Ref Type

Journal Article

PMID

(37980367)

Authors

Zhao JL, Antonarakis ES, Cheng HH, George DJ, Aggarwal R, Riedel E, Sumiyoshi T, Schonhoft JD, Anderson A, Mao N, Haywood S, Decker B, Curley T, Abida W, Feng FY, Knudsen K, Carver B, Lacouture ME, Wyatt AW, Rathkopf D

Title

Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC).

Journal	Vol	Issue	Date	Pages	Journal Short Title
British journal of cancer	130	1	2024 Jan	53-62	Br J Cancer

URL

Abstract Text

CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models.Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D. Secondary endpoints included PSA response, time-to-PSA progression, and radiographic progression.Common adverse effects included rash (31.7% Grades 1-2 (Gr); 31.7% Gr 3), pruritis (43.9% Gr 1-2), diarrhoea (37% Gr 1-2), and hypertension (17% Gr 1-2; 9.8% Gr 3). CC-115 RP2D was 5 mg twice a day. In 40 evaluable patients, 80% achieved ≥50% reduction in PSA (PSA50), and 58% achieved ≥90% reduction in PSA (PSA90) by 12 weeks. Median time-to-PSA progression was 14.7 months and median rPFS was 22.1 months. Stratification by PI3K alterations demonstrated a non-statistically significant trend towards improved PSA50 response (PSA50 of 94% vs. 67%, p = 0.08). Exploratory pre-clinical analysis suggested CC-115 inhibited mTOR pathway strongly, but may be insufficient to inhibit DNA-PK at RP2D.The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor.ClinicalTrials.gov identifier: NCT02833883.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN inact mut	castration-resistant prostate carcinoma	predicted - sensitive	CC-115 + Enzalutamide	Phase I	Actionable	In a Phase Ib trial, Xtandi (enzalutamide) plus CC-115 was safe and led to a PSA reduction >= 50% (PSA50) in 80% (32/40) and >=90% (PSA90) in 58% (23/40) of patients with metastatic castration-resistant prostate cancer at 12 weeks, and patients harboring PTEN mutation or deletion (n=11) achieved PSA50 of 91%, PSA90 of 55%, and median radiographic progression-free survival was not reached, compared to 75%, 55%, and 19.6 mo, respectively, in PTEN wild-type patients (n=20) (PMID: 37980367; NCT02833883).	37980367
PIK3CA act mut	castration-resistant prostate carcinoma	predicted - sensitive	CC-115 + Enzalutamide	Case Reports/Case Series	Actionable	In a Phase Ib trial, Xtandi (enzalutamide) plus CC-115 was safe and led to a PSA reduction >= 50% (PSA50) in 80% (32/40) and >=90% (PSA90) in 58% (23/40) of metastatic castration-resistant prostate cancer patients at 12 weeks, and patients with PIK3CA activating mutations or PTEN or TSC1/2 loss of function (n=16) achieved a PSA50, PSA90, and median radiographic progression-free survival of 94%, 63%, and 19.6 mo vs 67%, 47%, and 22.1 mo in PI3K pathway wild-type patients (n=15) (PMID: 37980367; NCT02833883).	37980367
TSC1 inact mut	castration-resistant prostate carcinoma	predicted - sensitive	CC-115 + Enzalutamide	Phase I	Actionable	In a Phase Ib trial, Xtandi (enzalutamide) plus CC-115 was safe and led to a PSA reduction >= 50% (PSA50) in 80% (32/40) and >=90% (PSA90) in 58% (23/40) of metastatic castration-resistant prostate cancer patients at 12 weeks, and patients with PIK3CA activating mutations or PTEN or TSC1/2 loss of function (n=16) achieved a PSA50, PSA90, and median radiographic progression-free survival of 94%, 63%, and 19.6 mo vs 67%, 47%, and 22.1 mo in PI3K pathway wild-type patients (n=15) (PMID: 37980367; NCT02833883).	37980367
TSC2 inact mut	castration-resistant prostate carcinoma	predicted - sensitive	CC-115 + Enzalutamide	Phase I	Actionable	In a Phase Ib trial, Xtandi (enzalutamide) plus CC-115 was safe and led to a PSA reduction >= 50% (PSA50) in 80% (32/40) and >=90% (PSA90) in 58% (23/40) of metastatic castration-resistant prostate cancer patients at 12 weeks, and patients with PIK3CA activating mutations or PTEN or TSC1/2 loss of function (n=16) achieved a PSA50, PSA90, and median radiographic progression-free survival of 94%, 63%, and 19.6 mo vs 67%, 47%, and 22.1 mo in PI3K pathway wild-type patients (n=15) (PMID: 37980367; NCT02833883).	37980367