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Researchers have uncovered several biological signs that may determine how metastatic castration-resistant prostate cancer (mCRPC) responds to a new treatment combination. The scientists made these discoveries as part of a phase III mCRPC trial investigating the effects of adding the drug ipatasertib to abiraterone, the standard of care.
Using a powerful sequencing technique to analyse tumour samples, the team showed that the addition of ipatasertib, an AKT inhibitor, helped certain groups of mCRPC patients – those whose cancer had specific genetic alterations – survive longer without the disease progressing. However, other patients did not benefit.
This knowledge could be used to help ensure that patients who are likely to benefit from the combination therapy receive it while others are spared unnecessary additional medication.
The study findings may also lead to new treatments for prostate cancer, as the identification of tumour genomic alterations associated with greater benefits revealed a biological pathway that researchers are now targeting in drug development work. Better treatment options are urgently needed for this condition, as the aggressive nature of the prostate cancer subtypes with these targeted alterations means that outcomes are generally poor.
Professor Johann de Bono, Head of the Division of Clinical Studies at The Institute of Cancer Research, London, was first author on the paper, which was published in the journal European Urology. The research was funded by Roche.
Outcomes are not consistent across the patient population
The trial, called IPATential150, enrolled 1,101 patients with previously untreated mCRPC. All of the participants received abiraterone, but while half of them received ipatasertib alongside it, the others were given a placebo instead.
Abiraterone, which was designed and developed at The Institute of Cancer Research (ICR), works by stopping the body from making testosterone, which prostate cancer uses to grow. Ipatasertib has a different mode of action, blocking the activity of a protein called AKT to inhibit cell proliferation and migration.
Overall, the addition of ipatasertib to the treatment regimen did not have a significant effect on the participants’ survival. At a median follow-up of 33.9 months, the median overall survival was only slightly longer in the ipatasertib group than in the placebo group – 39.4 months compared with 36.5 months.
However, when the researchers looked more closely at the most common genetic alterations across the patients’ tumour samples, they were able to associate certain characteristics with better or worse outcomes.
The importance of genetics
Of primary interest was the loss of PTEN gene function, which affects almost half of mCRPC patients and can occur due to genomic deletions or rearrangements. This gene suppresses the AKT signalling pathway that is often overactive in prostate cancer. The pathway regulates cell growth, survival and metabolism, and when dysregulated, it can promote the progression of the disease. Given that ipatasertib affects this pathway, the team were keen to see whether its addition to the treatment regimen led to better outcomes for this group of patients.
The researchers also investigated the PIK3CA/AKT1/PTEN pathway, which is known to be a major signalling pathway in multiple types of cancer. It has roles in controlling the survival and spread of cancer, as well as in managing the tumour environment. Analysis of the patients’ tumour samples revealed that the PIK3CA/AKT1/PTEN pathway was altered in 34 per cent of cases.
When the researchers compared the groups of patients with PTEN loss or PIK3CA/AKT1/PTEN pathway alterations with the other participants, they found that the addition of ipatasertib to abiraterone increased median overall survival by a more notable amount – from 29.2 months to 37.1 months.
This suggests that people whose tumours have these characteristics are likely to benefit from the ipatasertib-abiraterone combination treatment. This approach is not yet approved for clinical use, but the current research provides convincing evidence to support its use as a standard of care for certain patients.
Further research on the PIK3CA/AKT1/PTEN could also lead to new targeted medications that improve outcomes for more people with mCRPC.
“There is an urgent need for new treatments that improve outcomes”
Professor Johann de Bono, Regius Professor of Cancer Research and a Professor in Experimental Cancer Medicine at The Institute of Cancer Research (ICR) and The Royal Marsden NHS Foundation Trust, said:
“Many different genes can play a part in the development and progression of mCRPC, and the genetic changes across cells within the same tumour can be very diverse. As a result, patients typically develop treatment-resistant disease that is difficult to treat. There is an urgent need for new treatments that improve outcomes in these aggressive subtypes of prostate cancer.
“We are pleased that this trial – the first phase III trial of an AKT inhibitor, ipatasertib, with abiraterone in this type of prostate cancer – has uncovered new biomarkers that could help identify the patients most likely to benefit from this combination treatment.
“Further trials are needed to identify other groups of patients who may find this approach effective, but based on our findings, we believe that it could benefit about 12,000 people a year in the UK alone. The number of years of life saved could be extraordinary."