New Immune Therapy Boosts Disease Control in Prostate Cancer

 Adding an experimental immunotherapy to radiation treatment may extend disease-free survival in men with localized intermediate- or high-risk prostate cancer, according to a phase 3 trial.

The treatment, which has been fast-tracked by the FDA, has two steps: Intraprostatic injection of a replication-defective adenovirus carrying the herpes simplex virus thymidine kinase (HSV-tk) gene, followed by a course of valacyclovir. The viral enzyme then converts valacyclovir to a toxic metabolite that kills dividing cells, releasing tumor antigens that trigger an immune response.

If approved, this would be the first new therapy for men with localized prostate cancer in over 20 years, researchers led by Paul P. Tak, MD, PhD, of Candel Therapeutics in Needham, Massachusetts, wrote in The Lancet Oncology.

However, outside experts urged caution, citing concerns about the trial’s design and saying it’s too soon to judge whether the findings will translate into an overall survival benefit.

“One must walk a fine line between optimism and realism, especially when a biotech company is involved and trying to get and appease investors,” said Otis W. Brawley, MD, of Johns Hopkins University School of Medicine in Baltimore.

Around 30% of men with localized prostate cancer treated with curative-intent radiotherapy have disease recurrence, underscoring a need to improve local disease control.

In a phase 2 study, the experimental immunotherapy — called aglatimagene besadenovec or CAN-2409 — seemed to have synergistic effects in combination with radiotherapy. Among men with low- to high-risk prostate cancer, the combination produced a pathologic complete response rate topping 90%.

The new phase 3 trial included men planning to undergo definitive external beam radiation (EBRT) for intermediate-risk (85%) or high-risk (15%) prostate cancer. Of the former, more than 60% had unfavorable intermediate-risk disease.

Patients at 51 medical centers received either standard EBRT (78 Gy in two Gy fractions) or hypofractionated EBRT (60 Gy in three Gy fractions or 70 Gy in 2.5 Gy fractions). Short-course androgen-deprivation therapy (ADT) was optional.

The study team randomly assigned 496 men to receive aglatimagene plus valacyclovir and 249 men to receive placebo plus valacyclovir. Patients were given three ultrasound-guided injections of aglatimagene or placebo, at least 2 weeks apart; after each, they took oral valacyclovir for 14 days.

The primary endpoint was disease-free survival, defined as time from randomization to local failure, regional failure, distant metastases, or death from any cause.

After a median follow-up of 50 months, disease-free survival events had occurred in 31% of placebo patients vs 23% of those receiving aglatimagene. Median disease-free survival in the placebo arm was 86.1 months and not reached in the treatment arm (hazard ratio, 0.70; P = .016).

Any impact on overall survival remains to be seen. At the 50-month mark, death rates were similar in the trial arms, at 7% with aglatimagene and 6% with placebo. There were only two prostate cancer-related deaths, one in each group.

Treatment-related adverse events were more common with aglatimagene (74%) than with placebo (53%) and were most often flu-like symptoms. Serious treatment-related adverse events occurred in 2% of patients in both arms, including four cases of acute kidney injury in each group.

While the trial met its primary endpoint, the significance of that is questionable, according to Oliver Sartor, MD, who directs the Transformational Prostate Cancer Research Center at East Jefferson General Hospital in Metairie, Louisiana.

One issue he highlighted: ADT was optional in the trial, but it’s typically recommended for patients with high-risk or unfavorable intermediate-risk disease. Overall, 58% of trial participants with intermediate-risk disease received no ADT.

And subgroup analyses showed that only patients who did not receive ADT saw a significant reduction in disease-free survival events with aglatimagene.

“Where ADT was given,” Sartor said, “there was no clear benefit of the experimental treatment.”

He also raised concerns that the primary endpoint was “ too heterogenous for straightforward interpretation,” vs alternative endpoints such as metastasis-free survival, prostate cancer-specific survival, or overall survival.

Brawley had similar reservations about the endpoint of disease-free survival. He acknowledged the value of using shorter-term outcomes rather than waiting years for mortality data. But Brawley said, there have been “many instances” where a treatment looks promising based on surrogate endpoints, only to disappoint when long-term survival data become available.

Candel Therapeutics said it plans to submit a Biologics License Application for aglatimagene to the FDA in the fourth quarter of 2026.

The study was designed, conducted, and funded by Candel Therapeutics. Brawley disclosed serving on the board of several healthcare companies, none of which has a product involving prostate cancer treatment, and he consults for Grail on cancer screening issues. Sartor disclosed serving as a consultant to or received research funding from Bayer, Sanofi, AstraZeneca, and various other companies.

https://www.medscape.com/viewarticle/new-immune-therapy-boosts-disease-control-prostate-cancer-2026a1000kmn