Metastasis-free survival, PTEN loss explored in prostate cancer
medwireNews: Proffered paper presentations on prostate cancer at the ESMO 2016 Congress, held in Copenhagen, Denmark, covered metastasis-free survival (MFS) as a surrogate for overall survival (OS) in localised disease, and PTEN loss as a predictive biomarker for ipatasertib plus abiraterone therapy in metastatic castration-resistant prostate cancer (mCRPC).
Identifying the optimal OS surrogate in prostate cancer
Wanling Xie, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, opened the session by explaining that prostate cancer trials may take a decade to reach a “meaningful” OS primary endpoint and therefore a surrogate marker for outcome is required.
As part of the ICECaP international collaboration, her team collated information from 19 localised prostate cancer studies with long-term systemic follow-up and a total of 12,712 participants, looking at the relationship between MFS, defined as death from any cause or metastasis, and the true endpoint of OS, defined as death from any cause.
After a median follow-up of 10 years, OS and MFS rates were 42% and 45%, respectively, and after censoring for non-prostate cancer deaths, the rates of disease-specific survival (DSS) and time to metastases (TTM) were 11% and 17%, respectively.
At the patient level, MFS and OS significantly correlated, as did DSS and TTM, with Kendall’s Tau values of 0.91 for both. Five-year MFS significantly correlated with 8-year OS, with a R2 value of 0.83, while 8-year DSS significantly correlated with 5-year TTM with an R2 of 0.86.
And on a trial level, the treatment effect on MFS significantly correlated with the effect on OS, and the treatment effect on DSS with that of the treatment effect on TTM, with R2 values of 0.92 and 0.89, respectively.
For the correlation between MFS and OS, the HR was 0.88, so that a 12% or greater reduction in MFS would predict a risk reduction greater than 0 for OS, while the corresponding values for the treatment effect on TTM and DSS were 0.74 and 26%.
Xie therefore concluded that MFS is a valid surrogate for OS when assessing the impact of treatment on localised prostate cancer. And that the relationship between DSS and TTM “supports the notion that MFS and OS correlation is driven by [prostate cancer] events.”
Felix Feng, from the University of California, San Francisco in the USA, commented in a linked discussion session, that using MFS in the SWOG 8794 study would have identified the separation of the survival curve at 2.5 years compared with the 5.5 years it took with OS.
As MFS is the strongest surrogate marker of OS to date, Feng recommended that it should be used as the primary endpoint for future localised prostate cancer clinical trials. But he said that further research is required to quantify in the time saved by using MFS in trials and its impact on current studies of systemic therapy and those using improved imaging.
PTEN loss ‘predictive marker’ for mCRPC
Johann de Bono, from the Institute of Cancer Research in London, UK, reported on the relationship between PTEN loss – leading to heightened activation of the PI3K/Akt pathway – and response of docetaxel-treated mCRPC patients to the Akt inhibitor ipatasertib plus the anti-androgen therapy abiraterone.
As PTEN loss can result from a variety of genomic and nongenomic mechanisms, PTEN expression was measured in the trial using fluorescence in situ hybridisation (FISH) and next-generation sequencing (NGS), as well as immunohistochemistry, he explained.
As previously reported, the primary trial results in unselected patients failed to show improved overall survival with abiraterone plus ipatasertib 400 mg or 200 mg compared with placebo.
However, the current analysis showed that among patients with PTEN loss, radiographical progression-free survival (rPFS) was significantly better in patients who received the 400 mg dose of ipatasertib (median 11.5 vs 4.6 months, HR=0.39) or the 200 mg dose (median 11.1 vs 4.6 months, HR=0.46) than placebo-treated controls.
By contrast, there was no significant benefit for ipatasertib compared with placebo among patients with PTEN expression, de Bone said.
He concluded that this is “the first clinical evidence supporting PTEN loss as a predictive biomarker for benefit for mCRPC treated with ipatasertib plus abiraterone after docetaxel.”
Feng noted that while the current analyses were underpowered and therefore hypothesis generating only, the findings indicated a “substantial” rPFS benefit for ipatasertib for patients with PTEN loss in their tumour amples despite PTEN expression being known to be heterogeneous within patients and even within a single lesion.
Describing the findings as “provocative” and worthy of investigation in a phase III study, Feng concluded that “the trial highlights the future direction of treatment for mCRPC – biomarker-based personalization of therapy.”
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