Overview of Metastatic Castration Resistant Prostate Cancer (mCRPC)


An overview of metastatic castration-resistant prostate cancer (mCRPC) and the role of PSMA in mCRPC.

Alicia Morgans, MD: Welcome to the CURE Connections® program on radiopharmaceutical PSMA [prostate-specific membrane antigen]-targeted therapy for prostate cancer. My name is Alicia Morgans. I’m a medical oncologist and the medical director of the survivorship program at Dana-Farber Cancer Institute [in Boston, MA]. [Today], I have a panel of two physicians, a patient and a caregiver. I’d like to welcome my fellow panelists to introduce themselves.

Jeremie Calais, MD, MSc: I am Jeremie Calais. I’m a nuclear medicine physician. I specialize in cancer imaging and cancer diagnostics at UCLA [University of California, Los Angeles].

Matthew B. Rettig, MD: I’m Matt Rettig, a genitourinary medical oncologist. I specialize in cancers of the genitourinary tract, prostate cancer being the most common. I work at UCLA and the affiliated DA [delegation of authority], and I work with Dr Calais on PSMA diagnostics and therapeutics.

Joseph Wood: I’m Joseph Wood. I’m a long-time cancer patient with prostate cancer, and this is my [wife and] caregiver, Deborah Wood.

Deborah Wood: How do you do?

Alicia Morgans, MD: We will spend the next 60 to 70 minutes discussing the importance and emergence of PSMA-targeted therapy in prostate cancer, specifically in metastatic castration-resistant prostate cancer. Dr Rettig, would you provide us with an overview of prostate cancer with a focus on mCRPC?

Matthew B. Rettig, MD: Prostate cancer is the most commonly diagnosed cancer among men in the United States. It’s the second leading cause of cancer-related deaths behind lung cancer. The mortality [rate] from prostate cancer has been increasing over the last several years. In 2018, there were about 29,500 deaths due to prostate cancer in the United States, and in 2022, we’re expecting over 34,000, [maybe] even 34,500. Prostate cancer mortality is largely attributable to metastatic prostate cancer. That’s prostate cancer that has spread from the prostate to other organs, with bone being the most common site. When we treat advanced prostate cancer, the backbone of the treatment is aimed at decreasing the amount of testosterone. The terminology for that is not the most palatable: It’s called a medical castration. We lower the testosterone levels to a low range and often add [other] therapies. When patients [receive a diagnosis], we call [it] metastatic castration-sensitive, because the expectation is that almost all patients or their tumors will respond to the castration-based treatment. When the tumor evolves over time, it adapts to the castrated environment and becomes castration resistant, meaning no longer suppressed by low testosterone. It can grow and survive despite the low testosterone levels that are achieved by castration. Metastatic castration-resistant prostate cancer is the lethal event for this disease. [But] we’ve developed a lot of new therapies over the last 10 or 11 years that have increased life expectancy, and now we’re testing [them] earlier in the disease course to see if we can improve life expectancy even more.

Alicia Morgans, MD: Most prostate cancers are not diagnosed as advanced or metastatic prostate cancer. Can you give us [a] sense of how you think about diagnosing prostate cancer and how PSA [prostate-specific antigen] and other factors affect that process?

Matthew B. Rettig, MD: In the United States most patients are diagnosed with prostate cancer that’s localized. We do scans and don’t see evidence of the [cancer spread] to other organs, so we call [it] localized prostate cancer. In the United States, most cancers come to medical attention based on a PSA screening. PSA is a protein that’s secreted by prostate tissue. In normal prostates as well as cancerous prostate cells, that protein is secreted into the bloodstream. As [its level] goes higher above the normal background levels, it’s more likely to represent prostate cancer. An elevated PSA [level] often triggers a biopsy that can diagnose the cancer and ultimately lead to treatment. Treatment for localized prostate cancer is typically surgery and/or radiation, and sometimes hormone therapy is added. Ultimately, some patients with localized prostate cancer can have a recurrence and eventually develop metastatic disease.

Alicia Morgans, MD: There’s another important protein that I [want] to hear your thoughts on. It’s called PSMA. What’s the role of PSMA in prostate cancer and when do you see [its] expression?

Matthew B. Rettig, MD: PSA and PSMA sound similar, but they’re totally different. PSA is a prostate-specific antigen, and PSMA is [a] prostate-specific membrane antigen. The membrane is the wall of the cancer cell. It surrounds the cancer cell, and PSMA is embedded into the wall. It’s an important protein because it’s almost always expressed on cancer cells, and the amount of the expression or the amount that’s on the surface of the tumor cells, that’s on the membrane of the tumor cell, increases as the cancer progresses from localized disease to advanced and castration-resistant prostate cancer. It’s important because we can exploit this over-expression, this heightened amount of protein on the surface of the tumor cell, for the PSMA PET [positron emission tomography] scan as well as therapeutics to treat cancer cells and tumors in their most advanced stages.

Alicia Morgans, MD: As you mentioned, we can use that PSMA protein for imaging [and], potentially, targeting for treatment. Are all patients who have PSMA expression on their prostate cancer cells referred to a nuclear medicine specialist like Dr Calais for treatment or imaging, or is this something that’s a new and evolving space?

Matthew B. Rettig, MD: PSMA-based imaging is an evolving diagnostic arena. The FDA has approved PSMA imaging for two particular points in prostate cancer: the time a patient is diagnosed for what we call initial staging and the time when [a] patient who’s had surgery or radiation [has] a recurrence manifested by an [increased] PSA level, called a biochemical recurrence. A PSMA scan can be done to detect sites of recurrent cancer at the earliest stages. Those are the two on-label indications for its use, but we use it more in off-label indications when we’re testing different scenarios within prostate cancer and using it to monitor patient response to treatment.

Transcript edited for clarity.

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