PARP Inhibitors in Prostate Cancer - Episode 8

Biomarker Testing Protocols for Metastatic Prostate Cancer and What to Look For

Dr Morgans discusses biomarker testing protocols and signs to look for during testing.

Matthew Fowler: Your responses have started to touch on this topic already, but can you walk through the biomarker testing protocol and some of the types of biomarker testing you typically perform?

Alicia Morgans, MD, MPH: When I meet any patient with metastatic disease, we do germline testing or offer it. Not every patient agrees to it for a host of reasons, but we want to make sure individuals understand that it’s recommended and part of our clinical workflow. In our clinic, that’s done either by a blood draw in the clinic that day, which is an option for patients who prefer that, or by a saliva test that comes to the patient’s home, and the patient can provide the sample and send it back to the company directly. That workflow is a conversation at the first encounter, and then patients decide how they want to best proceed with that testing if they choose to.

Somatic testing is different for different patients. For patients who are young and have very high-volume metastatic hormone-sensitive disease, who seem to potentially have family members who may have prostate cancer, I try to get the testing done earlier on in that patient’s journey through treatment. Because I want to make sure I have the information as soon as I need it if the patient has progression of disease. For patients who have mCRPC [metastatic castration-resistant prostate cancer], if I’m encountering them after they’ve been through a few lines of therapy, I also want to get that testing done as soon as possible.

What varies in addition to the timing is where we do the testing, in terms of if it’s a new biopsy, or if it’s sent from the primary prostatectomy specimen or primary prostate biopsy specimen. That depends on the available tissue and the availability of biopsy material for metastatic testing, which can be hard if the patient has bone-only metastatic disease and isn’t typically how we would proceed. If a patient has a relatively easily accessible soft tissue disease or maybe a liver or lung lesion that we’re planning to biopsy anyway for histologic confirmation of metastatic disease and to ensure that the patient hasn’t had development of small cell histology, we’ll set up a biopsy and then send that tissue not just for pathology evaluation or pathologic evaluation but also for somatic tumor testing.

For patients who only have bone metastatic disease, we’ll do that as soon as we meet that patient if they have mCRPC. If they have only bone disease, we might send the primary prostatectomy specimen or a sample from prostate biopsies for testing. Because what we’re looking for in that situation in addition to MSI [microsatellite instability]–high status, which I mentioned before may make the patient eligible for pembrolizumab, is DNA-repair defect alterations, or things like BRCA1, BRCA2, ATM, PALB2, and CHEK2. These are what we call truncal mutations. We expect those to be there for most patients at the time of the development of the prostate cancer. They’re what’s driving it from the get-go and are typically going to be found in the prostatectomy specimen or those initial biopsies.

If we don’t have easy access to a prostatectomy specimen, or biopsy material is insufficient for testing, we can send a circulating tumor DNA specimen, which we would send with our germline genetic testing, because that’s how they get it. They assess circulating tumor DNA. They subtract what they find in the patient’s germline, and then the rest of it would be circulating tumor DNA. That’s an oversimplification, of course, but that can be a blood sample that we send in combination with our germline testing sample to try to find these mutations in patients who don’t have either archival tissue or an easily accessible metastatic site.

Matthew Fowler: What targets are you looking for in this testing? The big question is, which of them have therapeutic implications?

Alicia Morgans, MD, MPH: For germline testing, we’re looking for the DNA-repair defect mutations that can be involved with heritable cancer syndromes. These are typically things like BRCA1, BRCA2, PALB2, as well as the MSH and MLH mutations that can be associated with Lynch syndrome, because those can put patients at risk for MSI-high tumors or tumors with high TMB [tumor mutational burden] that could be targeted with pembrolizumab. The BRCA1, BRCA2, ATM, and other mutations that I mentioned are targetable with PARP inhibitors. At present, we have both olaparib and rucaparib approved for patients with metastatic CRPC with slightly different indications. Those are what we’re looking for.

For those mutations, those germline mutations are identifying 50% of patients who may be treated with PARP inhibitors, and the somatic alterations that we find identify another 50% of our mutations that may be targeted with PARP inhibitors, more or less. That’s not exact, but we find half of our patients with each of these testing options. Doing both gives us a much clearer picture of patients who may be eligible for targeted therapies.

This transcript has been edited for clarity.