Impact of Prior Radical Prostatectomy on Response to 177 PSMA-Lutetium Therapy and Survival Outcomes in Metastatic Castration-Resistant Prostate Cancer

For millions of men worldwide, a diagnosis of prostate cancer begins with a choice about how to stop the disease in its earliest stages. One of the most common ways to do this is a surgery called a radical prostatectomy, where the entire prostate gland is removed. For many, this cures the cancer. But for others, the disease returns, sometimes spreading to other parts of the body years later. When this happens, the cancer becomes resistant to the hormones that usually keep it in check, entering a difficult phase known as metastatic castration-resistant prostate cancer. Doctors have a powerful new tool to fight this advanced stage: a treatment that uses a tiny amount of radioactive material to seek out and destroy cancer cells. This treatment, which targets a specific protein found on the surface of prostate cancer cells, has changed the landscape of care. However, doctors have long wondered if the history of a patient's earlier treatments matters. Specifically, they wanted to know if having the prostate removed years ago changes how well the body responds to this new radioactive therapy compared to patients whose prostates are still intact.

A team of researchers at the Mayo Clinic set out to answer this question by looking back at the medical records of 260 men who received this radioactive treatment between 2018 and 2025. The scientists divided these men into two groups based on their surgical history. The first group consisted of 147 men who had undergone the prostate removal surgery years before their cancer returned. The second group included 113 men who still had their prostate glands when they started the new treatment. The researchers wanted to see if the men who had lost their prostates earlier in life responded differently to the therapy. They measured success in two ways: first, by checking if the level of a specific protein marker in the blood, known as PSA, dropped by at least half, and second, by tracking how long the men lived after starting the treatment.

The results showed a clear difference between the two groups. The men who had previously had their prostates removed were significantly more likely to see their cancer markers drop by half. About 55 percent of these men achieved this positive response, compared to only 34 percent of the men who still had their prostates. This was not just a simple coincidence; even when the researchers adjusted for other factors like age, the amount of cancer in the body, and the presence of cancer in the bones or organs, the history of surgery remained a strong predictor of a better response. The men with prior surgery were about twice as likely to see their PSA levels fall as expected. Furthermore, this group also lived longer. The data indicated that having the prostate removed earlier in life was linked to a lower risk of death, suggesting that the surgery might have altered the way the disease behaved over the long term.

The researchers considered several reasons why this might be happening. One possibility is that the prostate gland itself, when it is still present, acts like a sponge for the radioactive medicine. Because the healthy prostate tissue also contains the target protein, it might soak up a portion of the radioactive dose, leaving less of it available to travel to the cancer cells that have spread to other parts of the body. By removing the prostate years earlier, that "sponge" is gone, potentially allowing more of the treatment to reach the metastatic tumors. Another theory is that removing the primary tumor early on changes the biological nature of the cancer itself, perhaps preventing it from evolving into a more aggressive form that is harder to treat. The study did not prove exactly which of these mechanisms is at work, but it strongly suggests that the timing of local treatment matters.

The findings also helped rule out some other ideas. While the researchers initially looked at whether men who were born with widespread cancer (a condition called de novo metastatic disease) responded differently, they found that this factor did not explain the difference in outcomes once the surgery history was taken into account. The advantage belonged specifically to the group that had the surgery, regardless of how the cancer first appeared. The study also confirmed that other known factors, such as having cancer in the liver or other organs, or having very high levels of the PSA marker before treatment, were linked to poorer survival, which aligns with what doctors already knew about the disease.

This research adds a new layer of understanding to how doctors might plan care for prostate cancer. It suggests that the decision to remove the prostate, often made when the cancer is still confined to one area, may have consequences that echo for decades, influencing how well a patient responds to life-prolonging treatments much later in life. While the study was retrospective, meaning it looked at past data rather than following patients forward in time, the consistency of the results across different measurements gives weight to the conclusion. The authors emphasize that these findings do not yet change the standard of care, but they provide a strong reason for further investigation. Future studies will need to look more closely at how the radioactive medicine moves through the body and how the biology of the cancer changes after surgery to fully understand why removing the prostate early on appears to offer a lasting advantage.