Breakthrough combination therapy slows progression of prostate cancer

For men with the return of prostate cancer, a novel combined treatment can potentially give them an extended period before the cancer comes back.

Researchers at UCLA have found that a blend of a targeted radioligand drug and stereotactic body radiotherapy, or SBRT, more than doubles the life of men without making their cancer progress.

Prostate cancer ranks as the second most common cancer in men worldwide. While it has responded to initial treatment, it can recur in a relatively limited number of sites, a process known as oligorecurrent disease. SBRT previously was used to irradiate those new lesions accurately with minimal normal tissue sparing, delaying hormone therapy. But patients recrudesce because microscopic cancer cells evade imaging.

To find out, researchers at the Jonsson Comprehensive Cancer Center at UCLA did a test to find out if together, SBRT and a new experimental radioactive drug aimed at prostate-specific membrane antigen, or PSMA, would better control occult disease. Their phase 2 trial, the LUNAR trial, compared SBRT alone and SBRT with two shots of a radioligand drug called 177Lu-PNT2002.

The study enrolled 92 men with recurrent prostate cancer. Patients were randomly divided into two groups: one received SBRT alone, and the other received two injections of 177Lu-PNT2002 six to eight weeks apart followed by SBRT to all visible tumors. Researchers followed patients up with blood tests and PSMA PET scans and measured how long their cancer was kept in check.

The results were astounding. Patients who had the radioligand treatment prior to SBRT survived without disease recurrence for a median duration of 17.6 months versus 7.4 months in the patients treated with SBRT alone. The combined treatment decreased by 63% the risk of cancer relapse, needing hormone treatment, or mortality.

"This is the first randomized trial showing PSMA-targeting radioligand greatly increases time to progression when added to metastasis-directed radiation," said Dr. Amar Kishan, executive vice chair of radiation oncology at the David Geffen School of Medicine at UCLA and the study's first author. "It gives patients more time before hormone therapy is needed, which has potential huge side effects such as fatigue and bone loss."

Hormone therapy is a common treatment for prostate cancer that has spread, but it can significantly affect quality of life. The trial demonstrated that men who were treated with the combination therapy waited almost a year longer before requiring hormonal therapy—24.3 months versus 14.1 months for patients receiving radiation therapy alone.

Kishan emphasized that delaying the need for hormone therapy can maintain strength, energy, and bone density. "Avoiding or delaying hormonal therapy always improves quality of life," he stated.

Importantly, the study concluded that the incorporation of 177Lu-PNT2002 did not significantly affect side effects. A few men experienced moderate reductions in white blood cell counts, with no significant toxicities resulting from the treatment.

Lead author Dr. Jeremie Calais, director of the clinical research program at the Ahmanson Translational Theranostics Division, described how the study emphasizes the promise of PSMA-based theranostics—treatment and diagnosis combined in one strategy.

We employed PSMA PET imaging technology to provide SBRT aiming, which is more precise than other imaging technologies," Calais said. "And we combined it with PSMA radioligand therapy to treat the PSMA-expressing areas of disease, both the visible by PET and the microscopic areas too small to be visualized.".

The LUNAR trial is the first to attempt this approach in patients with advanced-stage recurrent prostate cancer. Previously, PSMA radioligand drugs had been used mainly for men with advanced disease that could no longer be treated.

Aside from clinical results, researchers also analyzed biological signs that might determine who would gain the most benefit. What they found was that patients with higher immune reactions—measured by changes in T-cell receptor activity—were less likely to see their cancer develop.

The researchers also discovered genetic differences in certain immune and DNA-repair genes that may help predict treatment success. These findings may ultimately be used to tailor treatments so that doctors can choose patients most likely to respond.

Despite this, approximately 64% of the men in the study eventually saw their cancer return. The researchers said this highlights how even in microscopic disease, the disease remains a big challenge in prostate cancer treatment.

This is a critical proof of principle," said Kishan. "It shows that maybe we can treat earlier with radioligand therapy and significantly change the disease course. And most importantly, we did not see considerably worse side effects with the addition of the drug.".

Calais agreed, noting that the trial illustrates how cooperation between radiation oncologists and nuclear medicine physicians can propel the treatment. "This is a wonderful piece of work demonstrating good collaboration," he said, "combining imaging with therapy at its best, theranostics."

The LUNAR trial reveals new hope for the treatment of men with recurrent prostate cancer before their disease is advanced. By combining high-resolution imaging with targeted radioligand therapy, doctors can target tumors visible and invisible to the eye, allowing patients to live longer and live better.

Future research can evaluate how long-lasting the benefit is, whether repeated treatment cycles add to remission length, and how genetic and immune profiles can personalize treatment.

If confirmed in larger studies, this two-way approach could revolutionize the early treatment of recurrent prostate cancer—giving men a longer, healthier life free of the harms of extended hormone therapy.

Research findings are available online in the journal ScienceDirect.

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