Can men with advanced prostate cancer avoid chemotherapy?

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

The drug

One such “radioligand” is now available for some prostate cancer patients. Called Lu-PSMA-617 (trade name Pluvicto), it carries a lethal payload of radioactive atoms. The drug binds to a cellular protein known as prostate-specific membrane antigen (PSMA), which is abundant on most prostate cancer cells but absent from most normal cells. Once attached to this protein, Lu-PSMA-617 delivers its radioactive cargo and then the target cell dies.

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

Doctors often respond by switching to a second-line hormone treatment that blocks testosterone in other ways. If these drugs do not work or become ineffective, then chemotherapy is usually the next option.

But can men with mCRPC skip chemotherapy — along with its challenging side effects — and start Lu-PSMA-617 right away? Researchers evaluated this potential strategy during a newly completed clinical trial.


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

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

The discoveries

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

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


Researchers still need to show that using Lu-PSMA-617 before chemotherapy actually prolongs survival before the FDA approves this new indication. Enrolled subjects are still being followed, and “hopefully, with further follow-up, this sequence of treatments may become more widely available,” said Dr. Mark B. Garnick, the Gorman Brothers Professor of Medicine at the School of Medicine. of Harvard and the Beth Israel Medical Clinic Center.

Dr. Garnick added, “This study marks another advance in our emerging treatment options for men with advanced prostate cancer and highlights the methodical advancement of pharmaceutical development.” When new therapies are introduced, they are tested in patients for whom treatment options are limited. Fortunately, Lu-PSMA-617 has shown excellent results in this population, and the research outlined here suggests that it may be able to advance this therapy to even earlier forms of advanced prostate cancer. We look forward to longer-term follow-up of this important study.”

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