Could men with advanced prostate cancer avoid chemotherapy?

When we think of radiation therapy, we usually imagine treatments targeted at tumors by a machine outside the body. Now imagine a different scenario—one in which radioactive particles injected into the bloodstream find and destroy individual cancer cells while leaving healthy cells unharmed.

The drug

One such “radioligand” is already available for certain patients with prostate cancer. It’s called Lu-PSMA-617 (trade name Pluvicto), and it contains a deadly load of radioactive atoms. The drug binds to a cellular protein called prostate-specific membrane antigen (PSMA), which is present in large amounts on most prostate cancer cells but not on most normal cells. After Lu-PSMA-617 sticks to this protein, it releases its radioactive cargo, and the target cell dies.

As it currently stands, Lu-PSMA-617 is only approved for a very specific circumstance: Eligible patients must have already been treated with chemotherapy for metastatic castration-resistant prostate cancer (mCRPC). In this advanced stage of the disease, PSA (prostate-specific antigen) levels rise despite treatments that block testosterone, a hormone that promotes prostate cancer growth (rising PSA levels indicate the cancer is progressing).

Doctors often respond by switching to second-line hormone treatments that block testosterone in other ways. If those drugs don’t work or become ineffective, chemotherapy is usually the next option.

But could men with mCRPC bypass chemotherapy — along with its difficult side effects — and start Lu-PSMA-617 right away? Researchers investigated this potential strategy during a recently completed clinical trial.

Could men with advanced prostate cancer avoid chemotherapy?

The Study

The PSMAfore Phase 3 trial enrolled 468 men with mCRPC. All of the men had PSMA-positive tumors, and each of them had already been treated with a second-line testosterone blocker. For most of the men, that drug was abiraterone; the rest had been treated with a drug called enzalutamide. None of the men had received prior chemotherapy.

The researchers randomly divided all of the enrolled men into two groups. The men in the treatment group received infusions of Lu-PSMA-617, while the men in the control group were switched to a second testosterone blocker that they had not yet received.

The results

After nearly a year and a half of follow-up, treatment with Lu-PSMA-617 produced promising results. Crucially, the treated men avoided further cancer progression for an average of one year, which was six months longer than in the control group.

Could men with advanced prostate cancer avoid chemotherapy?

Lu-PSMA-617 also led to significant PSA decreases: 58% of the men treated with Lu-PSMA-617 saw their PSA levels drop by half or more. Only 20% of men in the control group experienced comparable PSA declines. Lu-PSMA-617 was also well tolerated. The most common side effects were dry mouth and mild gastrointestinal symptoms, and treated men also reported less pain and better quality of life.


Researchers still need to prove that using Lu-PSMA-617 before chemotherapy actually extends survival before the FDA approves this new indication. Enrolled subjects will continue to be followed, and “hopefully this treatment sequence will become more widely available with further follow-up,” says Marc B. Garnick, MD, Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center.

Dr. Garnick added, “This study marks another advance in our new treatment options for men with advanced prostate cancer and underscores the methodological advances in drug development. When new therapies are introduced, they are studied in patients where treatment options are limited. Fortunately, Lu-PSMA-617 showed excellent results in this population, and the study described here suggests that this therapy may have translation to even earlier forms of advanced prostate cancer. We eagerly await longer-term follow-up of this important research.”