In October 2022, researchers from the Icahn School of Medicine at Mount Sinai and from Sema4, a health technology company, published a study on the clinical actionability and utilization of next-generation sequencing (NGS) for prostate cancer in a changing treatment landscape. They found that at Mount Sinai, the Food and Drug Administration (FDA) approval of poly-(ADP-ribose) polymerase (PARP) inhibitors for later-line treatment of metastatic prostate cancer increased the actionability of NGS findings but have yet to translate into earlier use of NGS testing.
GU Oncology Now spoke with co-author Tomi Jun, MD, medical director at Sema4, to better understand this finding and further illuminate the NGS landscape in its current state for prostate cancer.
What is the current benefit and ceiling for NGS testing in prostate cancer?
Dr. Jun: The value of a diagnostic test like NGS is really determined by the therapeutic landscape. Right now, PARP inhibitors are approved in advanced prostate cancer for patients with BRCA1/2 mutations and other homologous recombination repair (HRR)-related genes. Getting NGS can open up PARP inhibitors as a treatment option for patients. That’s the most actionable outcome, and that’s what clinicians are looking for.
There are some applications in the earlier stage as well. Some mutations, especially BRCA1/2, can have prognostic implications in early-stage prostate cancer and may justify a more aggressive approach.
In terms of the ceiling, there’s a lot more work to be done. I like to use the analogy of a microscope. The invention of the microscope allowed disease to be examined at a cellular level. Today, NGS is the microscope—though instead of cellular resolution, it provides molecular resolution. And NGS is still so new; we’re still in the research and discovery phase with it. There are only a handful of genes on the label for PARP inhibitors. There are around 20,000 genes in the human genome, and maybe 1000 of them are cancer-related (that we know of). We’re only at the tip of the iceberg. As research and discovery progresses, and as the treatment landscape expands, genomic information is going to become more and more actionable.
Why do you believe prostate cancer is slower than other malignancies, and even other solid tumors, in NGS uptake?
Dr. Jun: It comes back to the clinic, where physicians make treatment decisions. Advanced prostate cancer has been fortunate to have increasing treatment options, but genomic- or NGS-based testing hasn’t been needed to guide management until recently. PARP inhibitors are the first step in that direction for prostate cancer. By contrast, in lung cancer it has become the norm to do genomic testing upfront because it helps determine the patient’s first-line treatment options. Prostate cancer isn’t there yet, but the advent of PARP inhibitors is bringing NGS testing into focus for the community.
The other challenge that arises with prostate cancer is obtaining tissue for sequencing. Often, when PARP inhibitors are being considered for advanced disease, the primary tumor sample might have been obtained quite a while ago and at a different institution. Even if you do obtain and sequence the primary tumor, you have to wonder whether the cancer’s genomics have changed in the intervening time.
Alternatively, you can try for a new biopsy, but there may not be easily accessible biopsy sites, and bone metastases are hard to sequence. Plus, you don’t want to subject patients to more biopsies. Liquid biopsy can be a useful option for assessing tumor genomics noninvasively in these situations.
Ultimately, the uptake of NGS in prostate cancer will be driven by the development of more NGS-guided treatments. Until there are more NGS-guided treatments in earlier lines of therapy, the relevance of testing in earlier stages of disease will be more limited.
Your study found that at a single center, the FDA’s approval of PARP inhibitors for later-line metastatic prostate cancer did not lead to earlier use of NGS testing. Do you believe this finding is specific to the Mount Sinai hospital, or is there reason to believe it is generalizable to the larger population?
Dr. Jun: It is always difficult to generalize any results from a single center. We also had only about 1 year of follow-up on treatment patterns after the FDA approval, so I would view this as a snapshot of how NGS was being used at a single center around the time of the first PARP inhibitor approvals. Mount Sinai is an advanced academic center, so the physicians were already familiar with NGS and PARP inhibitors in prostate cancer. Many patients were being sequenced even before the FDA approval of PARP inhibitors, which may explain why we didn’t see a big change in NGS usage after the FDA approval. That is a quirk of the academic setting of the study.
Overall, I would expect to see a trend toward more frequent and earlier NGS usage as PARP inhibitor adoption increases throughout the prostate cancer community.
Do you believe that more PARP inhibitors coming to market will be linked with earlier use of NGS testing?
Dr. Jun: It’s not just the number of PARP inhibitors on the market, but also the line of therapy in which they are approved. There are some studies examining PARP inhibitors in combinations for metastatic hormone-sensitive prostate cancers, one of the earliest stages of metastatic disease. Currently, PARP inhibitors are only approved in the US after prior chemotherapy and/or androgen-directed therapy. So naturally, because these earlier lines of therapy don’t require NGS testing, physicians aren’t necessarily ordering the testing right away. But if we had a PARP inhibitor approved for patients with specific mutations in an upfront setting, physicians would be compelled to perform NGS testing earlier.
Can you speak to some of the other genes that figure to play a prominent role or other approaches to gene sequencing in prostate cancer?
Dr. Jun: There has been a lot of discussion about the HRR-related family of genes as well as genes beyond BRCA1/2 that are relevant for selecting patients for PARP inhibitors. Much more work needs to be done to make sure that we’re selecting the right patients for these therapies.
Another exciting area is the development of multi-omic biomarkers. This is where we go beyond single genes and use the full range of genomic data that NGS can provide to help guide treatment. At present, the application of NGS that most clinicians are familiar with is targeted sequencing panels that cover 300 to 500 genes. But it is now possible to do whole-exome or even whole-genome sequencing in the clinic.
This type of comprehensive genomic profiling could create new possibilities for management. There was some interesting work in Nature recently looking at whole-genome sequencing from circulating tumor DNA in prostate cancer. They were able to observe patients develop androgen receptor amplification over the course of their treatment—an example of tracking the development of treatment resistance at the molecular level. This raises the question of how would treatment decisions change if you knew a little ahead of time that the tumor was becoming resistant?
Are there any other details on NGS testing that are worth mentioning?
Dr. Jun: One item always worth mentioning and emphasizing is health equity and access. As we discuss the potential of these technologies, we need to make efforts to ensure that patients across the country, around the globe, have equitable access to them. There are so many challenges related to access, including financial considerations, logistics, education, etc. So, making sure we advocate for patients and physicians everywhere to be able to use and leverage these technologies and get the best care that they can is paramount.