Dr Feng Discusses Molecular Determinants of Response to APA in nmCRPC

Felix Feng, MD, University of California at San Francisco, Benioff Initiative for Prostate Cancer Research, discusses identifying molecular determinants of response to apalutamide in nonmetastatic castration-resistant prostate cancer in the SPARTAN trial. Thesee data were presented at the 2021 Virtual ASCO Genitourinary Cancers Symposium.

Transcript

My name is Felix Feng. I am a professor of radiation oncology, and urology, and medicine at the University of California at San Francisco. I also serve as the director for the Benioff Initiative for Prostate Cancer Research at UCSF.

Today, I will be discussing an abstract that I recently presented at ASCO GU on molecular determinants of response to apalutamide.

Our study focused on patients with non-metastatic castrate-resistant prostate cancer. Specifically, we profiled patient samples from the SPARTAN trial.

SPARTAN study was a Phase 3 study that enrolled 1,207 seven patients with non-metastatic castrate-resistant prostate cancer and randomized them to androgen deprivation therapy and placebo versus androgen deprivation therapy and apalutamide, which is a next-generation antiandrogen therapy.

SPARTAN was positive for its primary endpoint of metastasis-free survival but also positive for all other clinical endpoints assessed. We were able to retrieve samples from 233 patients that had enrolled on SPARTAN.

These samples were obtained from patient samples that are acquired on the average six to seven years before the patient was enrolled on the SPARTAN study, so they were older samples.

What we did was we applied a high-density gene expression array to the samples we had obtained. This expression array was made by Decipher and allows for the analysis of expression of every known protein coding gene, so over 46,000 genes.

What we then did well was we grouped the patients based on whether they had experienced long-term response to apalutamide on the SPARTAN study or whether they had early progression of disease on SPARTAN.

We looked for the biological signatures that were enriched in tumor samples from the long-term responders versus the early progressors. What we found was that number one, basal/luminal signatures were associated with a response to apalutamide.

While all patients, both basal and luminal, benefited from the addition of apalutamide to standard androgen deprivation therapy, the luminal patients appeared to have a better prognosis when treated with apalutamide than the basal patients.

The second thing we found was that certain immune cell activation signatures, and specifically, signatures associated with T-cell activation or IL-2 signaling were enriched in patients who had long-term response to apalutamide compared to the early progressors.

This is a super fascinating result, because it suggests that there might be some interplay between immune signaling and androgen therapy response.

What does this mean? Number one, it means that we should be looking at biomarkers of immune cell activation when we look at response to next-generation antiandrogen therapies.

The second thing is that samples that are old, six to seven years old before initiation of a patient on apalutamide, these samples contain enough of a biological signal to be able to predict that response to therapy many years later.

I think the true important take-home message is that the biology of a prostate cancer from a particular patient holds true over the course of many years.

One of the issues is that for patients with metastatic prostate cancer or non-metastatic castrate-resistant prostate cancer, sometimes, we have difficulty in obtaining patient samples, because we do not do fresh biopsies on these patients, oftentimes.

What this suggests is that when we are looking to predict response or resistance, we can go back and look at samples from many years prior, and that those samples will be informative. That is one of the major take-home clinical messages as well.

Another take-home message is that in the era of immunotherapy, potentially, we should be looking at these signatures of immune cell activation and potentially, these may help identify which patients we should test various immunotherapy agents on.

I want to stress that this is a hypothesis and that our study by no means suggests that we should be treating these patients with immunotherapy. It just suggests that there is potential difference in immune cell activation that might mediate or predict response to certain antiandrogen therapies.