Dr. Daniel George on HRR mutation testing patterns in mCRPC


“We're really looking at a situation where most of the HRR testing is happening when patients have already exhausted all other standard options,” says Daniel J. George, MD.

In this video, Daniel J. George, MD, highlights the background and key findings from the study, “Real-world homologous recombination repair mutation (HRRm) testing patterns in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in the United States,” which he presented at 2024 ASCO Genitourinary Cancers Symposium in San Francisco, California. George is the director of GU Oncology at Duke Cancer Center in Durham, North Carolina.

Video Transcript:

This study [is] really a retrospective, observational analysis of real-world practices around HRR testing in a broad US patient population. The reason for this was to understand where the current landscape is in terms of testing. We now have potentially actionable targets, and in particular targets that will be effective in patients who have HRR mutations, including BRCA1 and BRCA2, and non-BRCA HRR mutations. We partnered with the ConcertAI platform, which is a large national platform of oncology outcomes in largely community, but some academic centers. We looked over a broad landscape of time, from 2000 all the way to 2023, and recognized that most of that HRR testing is going to come in the last 4 or 5 years. Then we looked particularly in patients in the castrate resistant prostate cancer setting, because that's really where these alterations are actionable. We looked to see first, how many patients actually had detectable HRR mutations. We could find that. We didn't really have a denominator to see how many were tested negative, but we know in general in this patient population, it's going to be somewhere around 20% to 25% that are HRR positive. This is looking at both somatic tissue testing, as well as blood testing. Then we looked at the types of alterations. We found about 192 alterations present. About two-thirds of those were BRCA1 or BRCA2. Then the other one-third or so were HRR mutations. There were some that overlapped as well. So, we did have some patients that had both, of BRCA and non-BRCA alterations.

We looked at our demographics and everything, but the most important finding was the timing of this testing. We could see that from the time of metastatic castration-resistant disease to their last documented medical record in the ConcertAI database was on average about 2 to 2 and 1/2 years in these HRR-positive patients. When we looked at the time from their detection of HRR mutation to their last reportable node was about 8 to 10 months. So, these patients were being diagnosed with HRR alterations very late in the course, 18 months into castration-resistant disease that already progressed on traditional hormonal therapies, presumably on AR pathway inhibitors, and if they were going to get chemotherapy, probably that as well. We're really looking at a situation where most of the HRR testing is happening when patients have already exhausted all other standard options. The problem with that is that the best use of PARP inhibitors for these HRR mutations, in particular BRCA mutations, is going to be early in that castrate resistant disease, now with the latest indications in combination with their first AR pathway inhibitor. If we're not detecting these patients until they've got 8 to 10 months to live, we've missed the window where they’re most sensitive, most responsive, and where they can be used in combination. I think this points out the need to educate, to find these patients sooner, to help people recognize that anytime somebody has metastatic prostate cancer, has recurrent prostate cancer, or disease that is associated with a strong family history of breast cancer, prostate cancer, or pancreatic cancer, we want to do that testing. These are the patients we want to know even before we would want to be able to treat them in the castrate resistant setting. It will help us to plan that. It'll make sure that that transition happens timely. And then if we're going to use AR pathway inhibitors in that setting, we can do so together.

This transcription has been edited for clarity.

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