Targeting PSMA in Advanced Prostate Cancer - Episode 1

Evolution of Personalized Treatment in Advanced PC

March 30, 2021

Experts in genitourinary oncology specializing in advanced prostate cancer discuss the evolution of personalized approaches for patients with metastatic castration-resistant prostate cancer (mCRPC).

Ulka N. Vaishampayan, MBBS: Hello, and thank you for joining this Targeted Oncology™ presentation titled “Targeting PSMA in Advanced Prostate Cancer.”

Despite advances in treatment, patients with metastatic castration-resistant prostate cancer [mCRPC] eventually progress after cytotoxic chemotherapy and hormonal therapy. Strategies to improve outcomes for these patients are of great interest. Emerging research suggests that a radiopharmaceutical targeting prostate-specific membrane antigen [PSMA] is effective in this setting. Our discussion today will cover this research and other areas of interest in precision medicine for advanced prostate cancer. 

I am Dr Ulka Vaishampayan, a professor at the University of Michigan in Ann Arbor, Michigan. My field of research is clinical trials and development of novel therapeutics in GU [genitourinary] cancers, with a specific focus on advanced prostate cancer. Joining me is Dr Oliver Sartor, a professor of medicine and the assistant dean for oncology at Tulane University School of Medicine in New Orleans, Louisiana. Thank you for joining us, Oliver. Let’s begin.

Oliver Sartor, MD: Glad to be here. There are really good topics tonight for discussion, so I’m looking forward to the program.

Ulka N. Vaishampayan, MBBS: Let’s start by discussing the evolution of personalized treatment approaches for metastatic castration-resistant prostate cancer. Why is precision medicine complicated in prostate cancer, and what are the biggest challenges facing us?

Oliver Sartor, MD: It’s an interesting topic and 1 that has been very evolutionary. In 2018, we had the first precision medicine approach in prostate cancer. That was not just in prostate cancer. It was across any particular cancer in the use of either MSI [microsatellite instability]–high or mismatch repair deficiencies, when pembrolizumab could be used. That applied to prostate cancer, but it actually was the first FDA approval to cut across all histologies. Now you had a treatment for a biomarker instead of a treatment for a particular histology of cancer. Prostate was in that mix.

That’s very important from multiple perspectives, not the least of which being that some patients with prostate cancer can have dramatic responses with either MSI-high or mismatch repair deficiency. There has also been a modification to that approval, adding high tumor mutational burden. That was No. 1.

In May 2020, we ended up with a couple of more approvals based on precision medicine. One was rucaparib, and the other was olaparib. These are the PARP inhibitors. PARP inhibitors have been used in other cancers, but they were new to prostate cancer. As it turns out, these are also biomarker-driven therapies, and you have to have either homologous recombination repair deficiency for olaparib or, very specifically, BRCA1 or BRCA2 for rucaparib.

There are a couple of interesting things about the approval, and there has already been an evolution. No. 1 is that there were germline and somatic alterations approved. Germline in BRCA1 and BRCA2 were approved for rucaparib and olaparib, even though the olaparib study did not include germline as a specific biomarker. 

There was also subsequent evolution in August and November for circulating tumor DNA [ctDNA], very particularly used in the Foundation Medicine platform, to be able to detect these predictive biomarkers in either homologous recombination repair genes or BRCA1 or BRCA2 in particular, and again for the PARP inhibitor. That’s been the evolution to get us to this point.

Now we see potential evolution with things like PTEN altered prostate cancer, which has gotten a little play recently with an AKT inhibitor called ipatasertib. Then we have the phenotypic biomarkers that we’ll be talking about very shortly. There is a lot of movement in the biomarkers and a lot of good things. 

Let me briefly touch upon challenges. When you’re looking at somatic biomarkers in prostate cancer, you are often talking about obtaining tissue in a disease that is hard to obtain a tissue from. Sometimes all you have are a couple of little prostate biopsies that may date 8, 9, or 10 years. Going after those little slivers of tissue that are maybe at a community hospital and not even being able to find the tissue can be a real challenge. 

Unlike in ovarian cancer, which has relatively bulky peritoneal metastases studied, and things like that, this disease is associated with bone-only metastases a significant percentage of the time, as well as retroperitoneal lymph nodes, which are hard to sample. That’s 1 of the reasons the ctDNA is so important. Maybe that’s too much information, but that’s my initial foray into precision medicine.

Ulka N. Vaishampayan, MBBS: That’s a wonderful overview. I completely agree with you on some of the big challenges. That’s why prostate cancer, for such a common cancer, has lagged somewhat behind in having targeted therapies. It’s that we only have primary tumor tissue frequently available, and it’s not reflective of recently what’s going on with the metastatic cancer. That is definitely a challenge. The more we can develop liquid biopsies and ctDNA types of techniques to reflect what’s going on in real time with metastatic disease, the more we will improve our efficiency of the targeted therapies. 

Oliver Sartor, MD: I’d like to make a brief comment if you don’t mind. That is of a recent abstract at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] looking at concordance between the ctDNA and the tissue. Concordance was very high. For those who have been concerned that the circulating tumor DNA is inaccurate or incomplete, that’s always going to be a concern. Nevertheless, we have matching with tissue that looks pretty good, so that’s an important lesson to remember as we go forward.

Ulka N. Vaishampayan, MBBS: We’ll of course expand further later about the germline vs somatic mutations, when to get what, and what the indications are.

Transcript has been edited for clarity.