How genomic testing and molecular markers are improving the landscape of advanced prostate cancer

Alicia K. Morgans, MD, MPH

Biomarkers and genomics are becoming increasingly popular for the diagnosis and treatment of prostate cancer. More discussion and research continue to be conducted to improve the efficacy of and navigate these valuable methods of disease detection.

At the 2021 Society of Urologic Oncology Annual Meeting, a presentation was given by Alicia K. Morgans, MD, MPH, on the implementation of biomarkers and genomics in men with advanced prostate cancer.¹ In a recent interview, she summarizes the main point of her talk, “Advanced disease: Incorporating molecular markers and genomic studies into therapy,” and discusses the general growth occurring in the advanced prostate cancer space. Morgans is a genitourinary medical oncologist and medical director of the Survivorship Program at the Dana-Farber Cancer Institute in Boston, Massachusetts.

Could you provide a brief overview of your presentation and discuss some of its highlights?

This was really a presentation that focused on using genetic testing to try to identify patients who might be eligible for targeted therapies and, of course, who may need to have information to inform their family members of potential risk for heritable cancer syndromes. I started the presentation by explaining that there are so many advances in prostate cancer, many of which are actually targeted, including things targeting [prostate-specific membrane antigen] like lutetium, other CAR Ts, byte therapies, and multiple others. I couldn't get into everything in this presentation and [rather] focused on DNA repair defect alterations, and also patients who have [microsatellite instability (MSI)]-high status. We reviewed how these particular alterations are potentially targetable by PARP inhibitors for DNA repair defects or pembrolizumab [Keytuda] for MSI-high status, and then talked about how we actually would incorporate the testing involved to understand both germline DNA repair defect alterations, or tumor tissues, somatic alterations in DNA repair defects genes, or DNA repair defects. And also, thinking about MSI-high status or tumor mutational burden for patients who might be eligible for pembro[lizumab]. We concluded by really thinking about where these agents are going in the future. For PARP inhibitors, that includes combination therapies that I think are really exciting, and we'll hopefully hear some updates on how they may be coming to populations outside of those with only these DNA repair defects mutations by early next year.

Could you describe your own use of molecular markers and genomic studies in clinical practice?

I think that this is an area that needs to be really personalized to each clinical practice and needs to be thought about carefully, because our normal operating procedures in clinics do need to incorporate both germline and somatic testing for patients with metastatic disease in particular. So, in my practice, I work with a team that can actually counsel patients before germline genetic testing, for example, and that's simply a referral that I need to make. But in other practices where I've worked, I’ve worked with my nursing team to order these germline genetic tests from our clinical practice, because we had a different workflow, I think either option is fine. [When] my clinic ordered these tests, we did both blood-based tests as well as home-saliva-based tests for patients to do it themselves, and then we followed the results up with patients. For those patients who had DNA repair defect alterations, or any alteration that might signal a heritable cancer syndrome, we followed that with a genetic counselor appointment on the back end. That really seemed to flow nicely for our clinical practice. For practices that don't have genetic counselors, [they] could potentially integrate a chatbot or other support from the testing companies on the back end. In my current practice, where we're doing things with more counseling on the front end, that also works but does require a different resource availability to really enable that. Of course, tissue testing is happening through our nursing staff typically requesting pathologists to do [next-generation] sequencing on the samples that we have, whether they are new biopsy samples, if that's possible, or potentially from prostatectomy specimens. And in my practice, we use less circulating tumor DNA than in [others], but that is also something that I talked about in the discussion and something that is coming to our clinical practices. I tried to emphasize in the talk and do in my own practice, if I send circulating tumor DNA, I do want to make sure that it's for a patient who has a PSA that's rising and disease that is progressing. In settings where the PSA has gone down significantly and the disease seems to be under control, there may be less circulating tumor DNA and so we might miss alterations that are present simply because the disease is controlled. So, that involves a lot of steps and a lot of processes, and as we said, it's different for every practice. But these kinds of testing procedures and plans, I think, can be implemented hopefully in clinical practices more broadly.

What have been some of the notable highlights in the advanced prostate cancer space from 2021? What advances are you anticipating in 2022?

I think that we have seen a lot of updates and advances in advanced prostate cancer generally, one of the biggest of these being PSMA-targeted lutetium. And this is, of course, a radiopharmaceutical that was reported about in the VISION trial, and we are expecting that the FDA is reviewing this particular agent now and hopefully within the next few months we'll have some understanding of whether this will end up being an approved agent.

Another advance that I think we should acknowledge, that affects both advanced prostate cancer and high-risk, localized disease as well as recurrent disease, is imaging advances which are not necessarily therapeutics, but [have] really transformed the way that we think about the data and how we treat our patients. That can be from the time of diagnosis with localized disease, as well as biochemical recurrence. If the lutetium agent ends up being approved, we may have to use our PSMA-based imaging practices to actually identify patients who would be eligible for lutetium. So, imaging advances with PSMA-directed modalities, I think, are absolutely shifting the landscape. And finally, we have heard for other targeted therapies, like olaparib [Lynparza] in particular, that there may be a potential to use these agents in unselected populations. We only have a press release, but the PROPEL trial,² which was looking at patients with mCRPC who are newly getting this first-line treatment for mCRPC , [showed that these patients] may benefit from a combination of abiraterone [Zytiga] and olaparib vs abiraterone alone. The press release, at least, suggests that this could be in an unselected population. Exactly what the data is going to show and how this may be useful and applicable to populations that we see in clinic is not yet clear, but we are expecting that that data will be out to follow the press release that we've had so far already this year in 2021.

References

1. Morgans AK. Advanced disease: Incorporating molecular markers and genomic studies into therapy. Lecture presented at: 2021 Society of Urologic Oncology Annual Meeting; December 1-3, 2021; Orlando, Florida

2. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. PROPEL: A randomized, phase III trial evaluating efficacy and safety of Olaparib combined with abiraterone as first-line therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Published online February 26, 2019. Journal of Clinical Oncology. 37, no.7_suppl. doi:10.1200/JCO.2019.37.7_suppl.TPS340