Developments in Phenotypic Precision Medicine for Prostate Cancer

By Vanessa Ira - December 20, 2022

Jacqueline T. Brown, MD is a medical oncologist specializing in the treatment of patients with genitourinary malignancies at Winship Cancer Institute of Emory University in Atlanta, GA and an Assistant Professor within the Emory University School of Medicine. She is actively involved in clinical investigation of novel therapeutics in patients with genitourinary cancers in all phases of drug development and has a special interest in improving the management and quality of life of older patients with these cancers.

Dr. Brown sat with us to talk about current developments in phenotypic precision medicine for advanced hormone sensitive and castration-resistant prostate cancer.

What are some developments in phenotypic precision medicine for advanced hormone sensitive and castration-resistant prostate cancer?

Dr. Brown:  Absolutely. Some developments more recently, and I think we defined it as these are observable characteristics. So, I just want to name a few of those, and then pivot to what we’re excited about and what’s coming down the pike, what we’re using in clinical practice now and then what’s coming down the pike for these patients. When we are getting an initial biopsy, we’re seeing a patient, that patient perhaps has, depending… We’re looking at their scans and we’re saying, what is the distribution of their cancer? And like I said, the very typical patient with metastatic prostate cancer has lymph node metastases and perhaps bone metastases. It’s much rarer for you to see lung metastases and liver metastases, although we do see that. And when we see those findings in our patients, we get worried that perhaps we’re looking at a more aggressive variant of prostate adenocarcinoma or potentially even transformed prostate adenocarcinoma, like a neuroendocrine carcinoma transformed originally from prostate adenocarcinoma.

We’ll get a biopsy and we’re looking at that histology to tell us are we dealing with a neuroendocrine component to this tumor. That finding is going to influence our treatment. That patient, we know is going to be less responsive to hormone therapy and is going to be more responsive to a platinum doublet chemotherapy that we may not use for our typical patient. So, that is an example of phenotypic precision medicine, not one we typically think of. Even when we’re talking about, excuse me, when we’re talking about originally thinking about the initial approval of upfront docetaxel in patients with castration sensitive hormone, excuse me, castration-sensitive metastatic prostate cancer, we would often reach to single agent docetaxel in addition to ADT upfront, particularly for patients who had high-volume disease. And high-volume disease was defined as patients with four or more bone lesions or visceral disease. And so again, that is an example of phenotype precision medicine.

I think that, going forward, one, the aspect of phenotypic precision medicine that has most impacted our practice in the last year to two years, or slightly longer than that, is the appearance of advanced imaging in the form of PSMA PET scans. So, these are imaging where the radio tracer is specific for PSMA. And PSMA is a transmembrane protein found on greater than 80% of prostate cancer cells. And so, imaging, like PSMA PET scan, can be used to localize that molecule on prostate cancer cells. And we have multiple prospective clinical trials showing that this imaging modality has a higher sensitivity and specificity compared to conventional imaging, like cross-sectional CT scans, and bone scan.

And so, we use advanced imaging in several settings. We used advanced imaging, excuse me, in the setting of biochemically recurrent prostate cancer, which is where a patient has gone through curative intent therapy, be it surgery or radiation therapy, and then they have a PSA that drops to zero or near zero, and then starts to rise again. And so, there is a role for these advanced images, PSMA PET scans or other types of PET scans, in this setting. And so, what we’re doing is looking for what is making that PSA. So, PSA is a blood test that can be a proxy for what’s happening with the underlying cancer. And PSA is a protein made by prostate cancer.

So when we’re doing this scan, we’re trying to say, we see this rising PSA and this patient previously treated with curative intent. Is that coming from local recurrence? Is that coming from metastatic recurrence? Because, the distribution of the disease at the time of that imaging is really going to impact management, whether that patient has salvage local therapies that can be used if they only have local recurrence, or whether they really need systemic therapy because they have a more widespread systemic recurrence. And so, that’s a role for advanced PET imaging, particularly those looking at PSMA.

Another role, and I think this is coming into play even more recently, is the use of PSMA, and particularly Gallium-68 as the tracer in this study, linked to lutetium-177. This is a radioligand, which is used in conjunction with PSMA PET scan, which can deliver radiation therapy attached to a PSMA targeted antibody. And so, this agent, lutetium-177-PSMA-617, was approved in February of 2022 for patients with metastatic castration-resistant prostate cancer who have progressed after having received a prior novel hormonal agent as well as at least one taxane chemotherapy. So, this is an extremely exciting therapy that is now taking an image of a patient and determining what options we can use for them and has added this new tool to our toolbox to treat our patients. So, it’s very exciting.