Tthe phase III IPATential150 study met its co-primary endpoint of radiographic progression-free survival ( rPFS ) in patients with metastatic castration-resistant prostate cancer ( mCRPC ) and whose tumours had PTEN loss.
In this patient group, Ipatasertib in combination with Abiraterone and Prednisone / Prednisolone provided a statistically significant reduction in the risk of disease worsening or death, compared to current standard of care ( Abiraterone and Prednisone / Prednisolone ) plus placebo.
The other co-primary endpoint of rPFS in the overall study population ( ITT ) was not met.
The safety profile for the combination of Ipatasertib and Abiraterone was consistent with previous analyses and known risks.
While initial data are encouraging, overall survival ( OS ) benefit and additional secondary endpoints are not yet mature.
The trial will continue until the next planned analysis.
Ipatasertib is an oral, highly specific, investigational medicine designed to target and bind to all three isoforms of AKT ( protein kinase B ), which blocks the PI3K/AKT signalling pathway, a key driver of cancer cell growth and proliferation in prostate cancer.
The PI3K/AKT pathway has also been implicated in resistance to anti-androgen therapy as androgen receptor ( AR ) inhibition is associated with an increase in AKT pathway activation.
Functional loss of the tumour suppressor protein PTEN within the tumour, seen in approximately 40-60% of mCRPC patients, results in hyperactivation of the PI3K/AKT pathway and is associated with adverse outcomes such as increased tumour grade and stage, earlier biochemical recurrence after radical prostatectomy, metastasis, prostate-cancer-specific death, and androgen-independent progression.
Clinical development programme for Ipatasertib focuses on tumours that are frequently found to have activation of the PI3K/AKT pathway.
In addition to prostate cancer, Ipatasertib is being studied in certain types of breast cancer including triple-negative breast cancer ( TNBC ) and hormone-receptor positive ( HR+ ), HER2- negative breast cancer.
IPATential150 is a double-blind, placebo-controlled, randomised phase III study assessing Ipatasertib in combination with Abiraterone and Prednisone / Prednisolone, compared to placebo plus Abiraterone and Prednisone / Prednisolone, in adult male patients with asymptomatic or mildly symptomatic, previously untreated mCRPC.
The co-primary endpoints of the study are investigator-determined rPFS in the overall study population, as well as a subpopulation whose tumours have PTEN loss, as assessed by immunohistochemistry ( Ventana assay ).
Progression-free survival ( PFS ) in the study is defined as the time from date of randomisation to the first occurrence of disease progression or death from any cause, whichever occurs earlier. Secondary endpoints include overall survival, safety, time to pain progression, time to initiation of cytotoxic chemotherapy and time to function deterioration.
Prostate cancer is the second most frequent cancer and the fifth leading cause of death in men. Primary treatment of advanced prostate cancer is androgen deprivation therapy ( ADT ); however, up to one-third of patients will progress despite reduction in serum testosterone levels to castrate levels ( less than 50 ng/dL ), either through surgical or medical castration.
Castration-resistant prostate cancer ( CRPC ) is defined by disease progression, as measured by prostate specific antigen ( PSA ) or radiographic measures, despite adequate suppression of serum testosterone levels.
Despite the current availability of life-extending therapies for mCRPC, the majority of men will die of their disease: the median life expectancy in this population is less than three years.
Prostate cancer growth and survival is driven by abnormal AR signalling.
In CRPC, cell growth and proliferation is also commonly driven by activation of the PI3K/AKT signalling pathway. In particular, functional loss of the tumour suppressor protein PTEN within the tumour, seen in approximately 40-60% of people with mCRPC, results in hyperactivation of the PI3K/AKT pathway. PTEN loss is associated with adverse outcomes such as increased tumour grade and stage, earlier biochemical recurrence after radical prostatectomy, metastasis, prostate-cancer-specific death, and androgen-independent progression. The PI3K/AKT pathway has also been implicated in resistance to anti-androgen therapy as AR inhibition is associated with an increase in AKT pathway activation, suggesting that the tumour compensates for the loss of one pathway with another. ( Xagena )
Source: Roche, 2020