Precision Medicine for Prostate Cancer: The Role of Radiopharmaceuticals

3D rendering of prostate cancer

Radiopharmaceuticals have emerged as a significant tool in the treatment of prostate cancer, particularly in advanced stages. These medications are designed to deliver radiation directly to cancer cells, minimizing damage to healthy tissues.

New advances like combinations of radiopharmaceuticals and immunotherapy or new radioisotopes and delivery methods continue to move the field forward. However, challenges including moving radiopharmaceuticals into earlier disease stages and widespread access to these agents persist.

For Prostate Cancer Awareness Month, Jeffrey Y.C. Wong, MD, radiation oncologist and co-director of the Center for Theranostic Studies at City of Hope, discussed this evolving field and how treatment for prostate cancer continues to improve.

Targeted Oncology: What is prostate-specific membrane antigen [PSMA] imaging? How does it differ from other imaging methods for prostate cancer?

Jeffrey Y.C. Wong, MD

Wong: Imaging in prostate cancer has advanced with PSMA imaging. It is a form of PET imaging. Prior to PSMA imaging, the primary ways of imaging prostate cancer for potential metastatic disease were bone scans and CT scans. Those looked at changes in the anatomy to determine whether areas within the body had metastatic deposits. MRI scans are also important because they can identify potential deposits of cancer within the gland.

PSMA PET imaging is much more sensitive at picking up potential sites of disease. [Prostate-specific antigen (PSA)], which is a blood test that picks up prostate cancer in very early stages, was so sensitive that, many times, bone scans and CT scans were not picking out where that PSA was coming from. Now, PSMA PET scans can detect where [PSA] is coming from, so it is useful in screening patients to determine whether they have disease that has spread outside of the prostate gland to another part of the body, such as a bone, which is a primary site for metastases. It is also useful to determine whether disease has spread to nearby lymph nodes, [and] that may influence what therapies would be selected for that patient.

PSMA PET scans are also being looked at closely to identify the bulk of the tumor volume within the gland itself. People are looking closely at whether one could give selectively more radiation within the gland to the area of PSMA PET-positivity.

We can use these images to better select patients. For example, patients that have quite a bit of disease outside of the gland may not be the best candidates for surgery or radiation therapy to just the prostate gland. In patients that have limited disease seen on PSMA PET scan to the nearby lymph nodes, [PSMA PET scans] will help the radiation oncologist make sure that those nodes are included within the radiation field. It is an emerging example where many times patients are undergoing systemic therapies, usually androgen deprivation therapy, and there are times where a particular focus of tumor may not be responding as well as other sites. There is an emerging interest in using focused stereotactic body radiation therapy to those PSMA-positive sites in conjunction with systemic therapies.

The imaging is changing how radiation oncologists approach prostate cancer, and it is having an impact with regards to how other specialties approach prostate cancer. One example is these PSMA PET imaging agents are a way to predict or to screen patients that are most appropriate for radiopharmaceutical therapies directed against PSMA, and people are looking closely at whether the intensity of the uptake to a particular tumor can predict which patients would respond the best to PSMA-directed radiopharmaceutical therapy.

What situations would you be more likely to opt for radiopharmaceuticals for prostate cancer treatment vs systemic therapy?

It is an evolving area. Radiopharmaceutical therapies are a big addition to the types of therapy options we have for patients with prostate cancer. Radiopharmaceutical therapies currently are primarily for patients with metastatic disease. There are 2 basic radiopharmaceutical therapies that people focus on. One is radium-223 [Xofigo], which is what is called an alpha emitter that targets bone metastases. The PSMA-directed radiopharmaceutical therapy, in the form of the trade name Pluvicto [lutetium-177], targets prostate cancer by targeting PSMA. These agents were approved through clinical trials focused on patients with metastatic disease that had progressed or failed after standard therapies, including androgen deprivation therapy and chemotherapy, for example. The initial use of these agents was in that population.

What is the current situation for most patients is androgen deprivation therapy for metastatic prostate cancers. These radiopharmaceutical agents were reserved for patients that have gone through not just androgen deprivation therapy, but second-line therapy such as chemotherapy. What we are seeing more patients who would rather look at the radiopharmaceutical therapy as their next option after progression on androgen deprivation therapy.

What needs to happen are trials that closely look at whether radiopharmaceutical therapies can be moved earlier in the disease course, and those trials are ongoing. There are recent data that show that it may be appropriate to offer radiopharmaceutical therapy instead of chemotherapy in patients that progress after androgen deprivation therapy. Along those lines, there are clinical trials that are looking at using radiopharmaceutical therapy even earlier in the disease. Of course, those trials need to happen, and the results need to be published before it would change where we would use radiopharmaceutical therapies in the patient's disease course.

Are there any emerging agents in prostate cancer treatment that you are excited about?

The biggest area of interest is taking some of the same agents—or even new agents—that target prostate cancer, and instead of labeling with a radio label called a beta emitter like lutetium-177, we are looking closely at alpha emitters like actinium-225.

Alpha emitters have the potential to have more of an impact on tumor kill. They have properties that may not be as dependent on tumor radiosensitivity. It may not be as dependent in terms of how much tumor kill you see based on tumor hypoxia. Tumor hypoxia can potentially create a radio-resistant environment in a tumor. There are potential advantages for alpha emitters such as actinium-225.

Many trials are now looking at actinium-225 and radio-labeled agents targeted against prostate cancer. Most of the trials are in patients that have already had [lutetium-177], but some of the trials are now looking at patients getting these agents instead of [lutetium-177] and there is a population of patients who are not eligible for [lutetium-177] because they do not express PSMA. These newer agents, currently in trials, are being evaluated for that subpopulation of patients.

What do you consider to be the biggest unmet needs in prostate cancer?

These new radiopharmaceuticals are a big advance in terms of treatment for prostate cancer. Prostate cancer is a relatively radio-sensitive malignancy, and so it makes sense to develop these agents for the treatment of prostate cancer. We do know that these agents have a significant impact in terms of reducing PSA, helping reduce symptoms, and prevent or delay progression of disease, but the agent alone is probably not enough, and we need to find better ways to use these agents.

There are 2 basic strategies. One is to use the agents at an earlier stage of the patient's disease course when the tumor is less resistant to therapies and when there is less cancer to try to treat. Second, which I think has a lot of potential, is looking for ways to combine this form of therapy with other forms of cancer therapy. It will take a while to determine how best to use these new agents in an earlier disease setting or in combination with other therapies.

Another unmet need may not be specific to these agents. Having access to even the FDA-approved agents has been challenging, especially initially with rollout. The supply chain for the radionuclide needs to be as robust as possible to allow for access of these agents to patients that need this therapy. Along those lines, there needs to be increased access by increasing the number of physicians able to administer these agents, and that is an evolving area. These agents have proven to be so popular and effective that it has been a significant demand for this. That is stretching or challenging the ability of the specialties to deliver these agents.

We need more physicians, more access points, more centers—not only in the hospital bases, not only at the academic centers, but within the community. The community centers should be able to deliver these agents, and we need to work through that process. That is where most of the potential is. We have had other radiopharmaceuticals in the past that were FDA-approved for very radio-sensitive malignancies like lymphomas, and those agents were effective. Some have concluded that they are no longer used in the in the market because of lack of access and lack of providers providing those agents. We do not want to repeat the mistakes of the past.