New research has identified a way to predict resistance to a type of chemotherapy commonly used to treat advanced prostate cancer.
Using samples from more than 200 men with advanced prostate cancer, researchers found a significant association between chromosomal instability in circulating tumour cells (CTCs) – those shed from the primary tumour into the bloodstream – and worse outcomes from treatment with cabazitaxel.
In this study, the researchers show that assessing chromosomal instability in CTCs is feasible and can predict clinical outcomes, including survival and tumour response.
This simple marker could help doctors identify advanced prostate cancer patients unlikely to respond to cabazitaxel, therefore sparing them unnecessary toxicity and guiding them toward more effective options.
Genomic information is key to decision-making
For men living with metastatic castration-resistant prostate cancer (mCRPC), treatment decisions become increasingly complex as the disease progresses.
Most of these patients will already have gone through hormone-targeting therapies as well as chemotherapy.
When those options fail, oncologists face a difficult question: what next?
A common choice is cabazitaxel, a chemotherapy drug that has been proven to extend survival more than switching to another hormone-targeting agent.
A landmark study called the CARD trial, which recruited participants from more than 60 sites across 13 European countries, confirmed that cabazitaxel generally outperforms a second androgen receptor pathway inhibitor (ARPI) in this setting. This established it as the standard of care for patients progressing on docetaxel and ARPIs.
However, some men endure the harsh side effects of chemotherapy – which can include fatigue, infections and neuropathy – without gaining extra time. Until now, there has been no reliable way to predict who will benefit and who will not.
Analysing blood samples from advanced prostate cancer patients
The research team behind the current study analysed blood samples from participants in the CARD trial who had already received docetaxel and had progressed within 12 months of starting treatment with an ARPI.
CTCs are rare in whole blood, so the researchers used an innovative technique to isolate these cells without traditional enrichment methods such as immunomagnetic capture.
They treated four blood slides to remove red blood cells, stained them with fluorescent antibodies, and used semi-automated analysis to count CTCs among white blood cells.
They then used a proprietary algorithm that categorised cells as chromosomally unstable or ‘normal’ based solely on cell morphology.
Chromosomal instability matters
Advanced prostate cancer patients with high chromosomal instability in their CTCs had significantly worse outcomes. Median overall survival dropped from about 15 months in the low-instability group to just under nine months in the high-instability group.
However, the most clinically relevant insight was predictive: when chromosomal instability was high, cabazitaxel did not outperform switching to another hormone-targeting drug. In other words, for these patients, chemotherapy offered no advantage – only side effects.
This suggests that chromosomal instability in CTCs could serve as a biomarker to guide treatment decisions, helping doctors avoid ineffective chemotherapy and consider alternative strategies for certain patients.
Towards precision oncology for advanced prostate cancer
Ossian Longoria, the study’s lead and Clinical Research Fellow at the ICR, stated: “Clinicians rely on clinical trial outcomes from large studies such as CARD to guide decision-making for the majority of patients. However, predicting an individual’s response to treatment is the holy grail in oncology.
“Now, molecular markers are increasingly entering the picture, offering a deeper look at what drives each patient’s cancer.”
“Our findings build on decades of research at the ICR and elsewhere, and they represent a big breakthrough in the liquid biopsy and circulating tumour cell fields,” explained Professor Johann de Bono, a senior researcher and Regius Professor of Cancer Research at the ICR.
“This is the first prospective confirmation that chromosomal instability predicts cabazitaxel resistance in patients with advanced prostate cancer.”
