Expert perspectives on the utilization of genomic profiling in patients with metastatic castration-sensitive prostate cancer to impact treatment decisions.
Neeraj Agarwal, MD: We’re coming to the end, so I’d like to touch on genomic profiling of these patients before going to concluding remarks by all of you. Simon, how do you approach genetic testing? I’m talking about comprehensive genomic profiling of the tumor. All these patients should be referred to a high-risk genetics clinic for counseling to look for germline mutations. It’s clear that all patients with advanced prostate cancer may benefit from germline testing. I’m talking about comprehensive genomic profiling. How do you approach that topic in patients with metastatic CSPC [castration-sensitive prostate cancer]?
Simon Chowdhury, MD: [I approach it] with great trepidation and by asking experts like yourself and other people who understand the genomic field much better than I do. Genomics is complicated, so we sometimes oversimplify it. Basically, there’s germline genomic profiling and somatic genomic profiling. With somatic genomic profiling, it’s difficult. We see from the PROfound study, which you were involved with, with olaparib, that a lot of patients failed FoundationOne testing. A lot of samples had insufficient DNA extraction. That’s something we need to be aware of. If we have a patient with metastatic disease, particularly poor-prognosis metastatic disease, we need to get the DNA to check whether they have somatic mutations or germline mutations. Those patients will need options going forward, potentially a PARP inhibitor. That’s 1 aspect.
From the germline side of things, the NCCN [National Comprehensive Cancer Network] Guidelines are good. But to be honest, we don’t have the capacity of geneticists in the United Kingdom to go there for every high-risk localized patient. One has to be a bit more pragmatic and look at high-risk groups, such as Ashkenazi Jews, and patients with a significant history of likely BRCA-related cancers, and educate around that. It’s an evolving field. There are evolving tests. As you’ve probably heard a few times, my mantra is not that all genes are equal. BRCA1, BRCA2, ATM are very different genes with very different actionability. Not all mutations are equal, so homozygous deletion vs missense is very different. Not all tests are equal. We must be very careful about tests that call mutations that aren’t actionable. There’s a lot of work to be done. Maybe it’s chapter 2 of a big book. It’s an interesting area, and you and your group demonstrated with olaparib that there’s actionability that can benefit patients. These are exciting times, but it’s early.
Neeraj Agarwal, MD: I always learn when you talk about genomic profiling, so thank you for doing that. Ben, in a busy urology practice, how do you approach comprehensive genomic profiling of the tumor? Thirty percent of patients who were trying to get onto the PROfound trial in the mCRPC [metastatic castration-resistant prostate cancer] setting weren’t eligible for screening because the quality or quantity of tumor DNA was gone by the time they developed castration-refractory prostate cancer. Given those data, how do you approach CGP [comprehensive genomic profiling] in your practice for patients with metastatic castration-sensitive prostate cancer?
Benjamin Lowentritt, MD: That’s a great point. I was a trial site for PROfound, but I got 0 patients because all my samples failed. This informed how I started doing testing. Even though it’s not in an actionable time, based on some of those data I’m getting with the fresher biopsies at diagnosis, I’m getting an initial somatic work-up. If the tissue is fresh, it’s more likely to be successful. We have more of it, so we can do it off the biopsy specimen. Certainly, if there’s a prostatectomy out there, that makes it easier. For most patients we diagnose with de novo metastatic disease, we’re going to biopsy. I’m getting it up front with the understanding that many of these become actionable mutations in the future as the patients progress. Those are often present at the time of diagnosis and don’t tend to change. They’re called truncal mutations.
My approach is to test early and often. It’s election season in the United States, so it’s like voting. We must recognize that most of that information that we know is helpful, and it’s available at the beginning. Future discovery is going to be based on resistant mechanisms and other things developing over time, so we can’t not test as patients progress. In my practice those are often liquid tests and others are for patients progressing later in therapy. But I’ve gone to a lot more testing in the de novo setting.
Neeraj Agarwal, MD: I have a similar practice. I test for tumor somatic mutations in every patient who presents to me with metastatic castration-sensitive prostate cancer, because the quality or quantity of tumor DNA will probably not remain intact to allow a successful comprehensive genomic profiling, especially when many patients have bone-only metastases. When they’re progressing at castration-resistant disease onset, we don’t have enough time or opportunity to profile these patients. It’s always good to get genomic profiling done. Document the results in notes so that when they have progression to mCRPC, we can start the preauthorization for PARP inhibitors if they have DNA-repair mutations. Or we can get them enrolled in the clinical trials if they’re PTEN deficient or if they have other mutations. At least I’m not relying on or delaying the next line of treatment when they’re progressing. Thank you for sharing that experience from a busy urology practice.
Transcript edited for clarity.