High Decipher score is predictive of docetaxel benefit in advanced prostate cancer

In this interview, Gerhardt Attard, MD, PhD, FRCP, discusses the study, “Decipher mRNA score for prediction of survival benefit from docetaxel at start of androgen deprivation therapy (ADT) for advanced prostate cancer (PC): An ancillary study of the STAMPEDE docetaxel trials,”1 (NCT00268476) which was presented at the 2024 European Society for Medical Oncology Congress in Barcelona, Spain. Attard is a medical oncologist at University College London in the United Kingdom.

Gerhardt Attard, MD, PhD, FRCP

Could you describe the background/rationale for conducting this research?

Patients with metastatic prostate cancer are now treated with intensified hormone treatment. So, they receive injections every 3 to 6 months and then androgen receptor pathway inhibitors [ARPIs], and there are 4 or 5 that are used routinely. The outcomes for some are very good, and for some patients are not good. In fact, the natural history and prognosis are highly variable. As a community, we're looking at better ways to improve outcomes, and one way to achieve that, potentially, is docetaxel chemotherapy.

We've never tested the question of [randomly assigning] patients [who are] receiving ADT and an ARPI to docetaxel or no docetaxel, but many in the community believe docetaxel will improve patients' life expectancy. However, we know with certainty that docetaxel impacts quality of life significantly within 16 months. We've also shown in an analysis in STAMPEDE [NCT00268476] that after 18 months, quality of life remains reduced. We have worked for about 7 or 8 years now to identify predictive biomarkers that identify docetaxel-sensitive cancers. That could allow physicians to choose which patients would have intensified docetaxel chemotherapy and tilt the balance in favor of potential benefits, outweighing the risks.

To do this, we analyzed diagnostic tumor samples from just over 1500 patients who were randomized in 2 trials in the STAMPEDE platform protocol. Patients were [randomly assigned to] ADT [with or without] abiraterone, and half were [randomly assigned] to ADT with or without docetaxel. Together with our partners at Veracyte, we generated expression values for all genes in the transcriptome. We then extracted a signature. In fact, we've extracted a number of signatures, and focused on 59. Before looking at the data, we prespecified Decipher as a signature of interest for prediction of docetaxel effect. This is based on pilot data we generated in a training set in another trial called CHAARTED [NCT00309985].

What were the key findings from this study?

[At ESMO], we presented the results of this analysis, and we show that patients who have a high Decipher score derive significant benefit from docetaxel. The hazard ratio in that group is about 0.6. For patients in the low Decipher group, there's no evidence of benefit from docetaxel treatment. That hazard ratio is close to 1. We, probably for the first time in the context of docetaxel chemotherapy, have a statistically significant interaction P value. What this means is that there is statistical certainty that the benefits of docetaxel differ by the Decipher test.

We are currently using metastatic volume, the number of metastases on conventional scans, to make the decision on whether to treat someone with docetaxel or not. We show in an exploratory way that this greater effect with high Decipher is consistent regardless of metastatic volume. So, both in the high-volume patients and in the low-volume patients. The debate will now center on whether they should be implemented into clinical practice. Views will differ. Do we need to prospectively re-validate this in a large, randomized trial over the next 5 to 10 years, or can we use this data in isolation, potentially with other retrospective studies—and I've mentioned CHAARTED—to change our clinical practice? I think that's what we'll debate further over the next few weeks. My view is that these data are so strong we should be starting to act on it. But of course, there are nuances, and there are differences in access globally. There are a number of considerations to be made in that regard.

Could you expand on how these findings could impact clinical management of metastatic prostate cancer?

This is a test that is already available in clinical labs, so it can be feasibly performed on a diagnostic biopsy, which physicians have easy access to at diagnosis of metastatic disease. Then, based on the score, physicians could use that to decide whether a patient is given chemotherapy. Of course, this needs to be taken in the context of a range of clinical factors. In patients who are not fit for chemotherapy, this is not relevant.

There's also the important point about prognostication. At the start of our interview, I said that the disease course is highly variable. In fact, in a paper we published in The Lancet Oncology last year, we showed that 25% of these patients are in complete remission after 8 years after starting treatment. Now clearly, administering chemotherapy to a patient who has such a long period of remission is only going to impact quality of life without making a difference on their cancer-specific prognosis. There are a number of factors that need to be taken into account. But for physicians considering chemotherapy for which there is equipoise, the Decipher test could be used to swing the decision one way or the other.

How does this study contribute to the broader understanding of personalized medicine in urology?

It's no understatement to say introducing personalized medicine is a big task, logistically, scientifically, and pulling all the pieces together to achieve that. So, we've done this in a large trial across 105 UK centers in more than 1500 patients tested in clinical-grade labs. I think, in terms of translating a research result into clinical practice, this is 1 step ahead. But clearly, we would benefit from additional studies that reinforce or validate this result and build on this. What I envision is that the Decipher score, together with other signatures we have generated in the study that we’ll present in the near future and other testing modalities, such as next-generation sequencing for specific alterations in genes such as BRCA, will be pulled together to decide whether a patient receives chemotherapy, whether a patient receives a PARP inhibitor, or whether alternative treatment options should be employed.

Is there any future work planned based on this study?

There are a number of other signatures that we have studied, which are exploratory, but they're giving us interesting biological information. We're starting to understand why some cancers do badly, why others do very well, and identify specific biological pathways that associate those differences. So, more work to follow.

Reference

1. Grist E, Dutey-Magni P, Mendes L, et al. Decipher mRNA score for prediction of survival benefit from docetaxel at start of androgen deprivation therapy (ADT) for advanced prostate cancer (PC): An ancillary study of the STAMPEDE docetaxel trials. Presented at: 2024 European Society for Medical Oncology Congress. Barcelona, Spain. September 13-17, 2024. Abstract 1596O. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2024_abstracts/1596O.html.pdf