A new standard of care for rising PSA levels after prostate cancer treatment

It’s not often that a study leads to fundamental changes in the way cancer patients are treated. But new research is doing just that for some men with prostate cancer that returns after initial treatment.

Recurrence after treatment

The first sign of recurrence is usually a rise in blood levels of prostate-specific antigen (PSA). PSA levels should drop to zero after surgical removal of the prostate and to nearly zero after radiation therapy. Prostate cancer cells release PSA, so if the level rises again after that initial treatment, new tumors are likely forming in the body. This is called biochemical recurrence because the new tumors that form are still too small to be seen on traditional imaging scans.

Doctors typically treat biochemical recurrence with hormone therapies, which are drugs that stop the body from producing testosterone (a hormone that promotes prostate cancer growth). But results from a large clinical trial show there is a better approach.

Study methodology and results

In the study, called the EMBARK phase 3 clinical trial, researchers enrolled 1,068 men whose PSA levels had doubled within nine months of initial treatment. When PSA levels rise that quickly, men are at high risk for rapid cancer progression.

The men were randomly divided into three groups: One was treated with a hormone therapy called leuprolide, injected every 12 weeks. A second group was treated with leuprolide plus a daily oral dose of enzalutamide, a drug that diverts testosterone from its cell receptor. The third group was treated with enzalutamide alone, given daily.

A new standard of care for rising PSA levels after prostate cancer treatment

The researchers already knew from previous studies that enzalutamide slows further progression and prolongs survival in men with metastatic prostate cancer. With this new study, they hypothesized that earlier use of this drug might have similar benefits for men with biochemical recurrence.

That hypothesis proved correct. The men were followed for just over five years after completing their treatments. And according to the results, more of the men treated with enzalutamide were spared cancer worsening. Specifically, 87.5% of men who received the combination treatment—and 80% of men treated with enzalutamide alone—avoided metastatic cancer, compared with 71.4% of men who received leuprolide alone.

Enzalutamide treatment was also more effective at preventing further PSA increases. Overall, 97.4% of men who received the combination therapy and 88.9% of men who received enzalutamide alone avoided PSA progression, compared with 70% of men treated with leuprolide. If PSA levels were below 0.2 ng per milliliter after 36 weeks, men could stop treatment altogether. Far more of the men treated with enzalutamide (up to 90%) stopped treatment for up to 20 months.

Enzalutamide treatment was well tolerated. The most common side effects were mild to moderate nipple pain and breast enlargement. Most men in all three groups are still alive, and EMBARK researchers are following them to see if treatment-related differences in survival emerge over time.

Observations and comments

Based on the EMBARK results, Neal Shore, MD, director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina, and co-leader of the study, concluded that enzalutamide treatment “should now be the standard of care for high-risk biochemical recurrence.” Whether enzalutamide treatment should also be combined with leuprolide is a decision that men can make in consultation with a doctor.

A new standard of care for rising PSA levels after prostate cancer treatment

One important point is that doctors now have a better way of detecting metastatic prostate cancer that was not available when EMBARK was introduced. The cancer cells contain high levels of a protein called prostate membrane-specific antigen (PSMA), which becomes visible on special imaging scans. PSMA-based imaging techniques can reveal tiny metastatic tumors in the body that were not previously visible. In such cases, patients who would previously have been diagnosed with biochemical recurrence are now known to have metastatic cancer. And because doctors can now see these tumors, they can treat them directly with surgery. ion or radiation – and possibly achieve a cure.

Still, Dr. Stephen Freedland, EMBARK lead investigator and a urologist at Cedars-Sinai Medical Center in Los Angeles and Durham VA Medical Center in Durham, North Carolina, says the study’s findings still hold. If PSMA results are negative even though PSA continues to rise, “then EMBARK shows that systemic treatment [with enzalutamide with or without hormone therapy] is still the best option,” he says.

If PSMA results show only a few metastatic tumors (this is called oligometastatic prostate cancer), those tumors can be treated surgically or with radiation and possibly hormone therapy. And if PSMA shows widespread metastatic cancer throughout the body, then “metastasis-directed therapy is no longer an option and hormone therapy with enzalutamide is the best option to delay progression, as shown in EMBARK,” Dr. Freedland says.

This study looks at a very large portion of the treated prostate cancer population – those who still have residual cancer after surgery or radiation therapy – and the results are “encouraging and surprising,” says Dr. Marc Garnick, Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center. “Also encouraging is the ability for men to stop therapy if their PSA levels were low at the end of 36 weeks of therapy. As both Dr. Shore and Dr. Freedland emphasized, their study makes a significant contribution to this large patient population. The authors deserve great praise for this important contribution.”