Researchers have uncovered several biomarkers that may predict how patients with metastatic castration-resistant prostate cancer will respond to the novel combination of ipatasertib and abiraterone, according to a recent study published by Bono et al in European Urology.
Background
Prostate cancer uses testosterone to grow. Because of the aggressive nature of some prostate cancer subtypes with genetic alterations, outcomes are generally poor.
Abiraterone—which is currently the standard of care for metastatic castration-resistant prostate cancer—works by preventing the body from producing testosterone. Ipatasertib blocks the activity of the AKT protein to inhibit cell proliferation and migration. The AKT signaling pathway is often overactive in prostate cancer. The pathway regulates cell growth, survival, and metabolism and can promote the progression of prostate cancer when dysregulated.
“Many different genes can play a part in the development and progression of [metastatic castration-resistant prostate cancer], and the genetic changes across cells within the same tumor 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,” stressed lead study author Johann de Bono, MSc, PhD, Regius Professor of Cancer Research, Professor of Experimental Cancer Medicine, and Head of the Division of Clinical Studies at The Institute of Cancer Research in London and The Royal Marsden National Health Service Foundation Trust.
Study Methods and Results
In the phase III IPATential150 trial, the researchers examined survival rates among 1,101 patients with previously untreated metastatic castration-resistant prostate cancer who received either abiraterone plus ipatasertib or abiraterone plus placebo.
Overall, the addition of ipatasertib to the treatment regimen did not have a significant effect on the patients’ survival. After a median follow-up of 33.9 months, the median overall survival was only slightly longer in the patients in the abiraterone plus ipatasertib group compared with those in the abiraterone plus placebo group (39.4 months vs 36.5 months). However, the researchers discovered that the addition of ipatasertib to abiraterone helped some patients who had specific genetic alterations survive longer without disease progression.
Of primary interest was the loss of PTEN gene function, which is known to affect nearly 50% of all patients with metastatic castration-resistant prostate cancer and can occur as a result of genomic deletions or rearrangements. The PTEN gene suppresses the AKT signaling pathway. The researchers sought to better understand whether the addition of ipatasertib to abiraterone could lead to positive outcomes.
They also investigated the PIK3CA/AKT1/PTEN pathway, a major signaling pathway in multiple types of cancers that is known to control the survival and spread of cancer and manage the tumor environment. After using a sequencing technique to analyze the patients’ tumor samples, the researchers found that the PIK3CA/AKT1/PTEN pathway was altered in 34% of the cases.
They compared the groups of patients with PTEN loss or PIK3CA/AKT1/PTEN pathway alterations with the other participants and discovered that the addition of ipatasertib to abiraterone increased median overall survival from 29.2 months to 37.1 months. The researchers noted that the findings suggested that patients with these tumor characteristics may be likely to benefit from the combination of ipatasertib and abiraterone. Although the approach is not yet approved for clinical use, the current research provided evidence to support its use as a standard of care among certain patients.
Conclusions
The findings could help ensure that patients who are likely to benefit receive the novel combination therapy while other patients are spared unnecessary additional treatment. Future studies exploring the PIK3CA/AKT1/PTEN pathway may also lead to the development of new treatments for prostate cancer, since the identification of tumor genomic alterations associated with greater benefits revealed a biological pathway that researchers can target in drug development. More effective treatment options are critical to improving outcomes in prostate cancer.
“We are pleased that this trial … has uncovered new biomarkers that could help identify the patients most likely to benefit from this combination treatment,” Dr. de Bono underscored. “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 [patients with metastatic castration-resistant prostate cancer]. The number of years of life saved could be extraordinary," he concluded.
Disclosure: The research in this study was funded by Roche. For full disclosures of the study authors, visit sciencedirect.com.
