Combination treatment improves progression-free survival in patients with oligometastatic prostate cancer

Researchers from The University of Texas MD Anderson Cancer Center demonstrated that adding metastasis-directed radiation therapy to intermittent hormone therapy improved progression-free survival (PFS) in patients with oligometastatic prostate cancer. Findings from the multicenter EXTEND trial were presented today at the 2022 American Society for Radiation Oncology (ASTRO) Annual Meeting.

At a median follow-up of 22.1 months, the median PFS had not yet been reached in men who received the combination therapy, suggesting a significant improvement over the median PFS of 15.8 months in men who received only hormone therapy. The combination was well-tolerated and lengthened the period men could maintain a break from hormone therapy without progression, suggesting this approach could improve the quality of life for men with advanced prostate cancer.

We know that radiation technology has evolved to directly target metastases, to reduce side effects and to better treat men with prostate cancer. This study provides much needed data on the benefits of combining these newer radiation techniques with hormone therapy to improve outcomes."

Chad Tang, M.D., Principal Investigator, Associate Professor of Radiation Oncology

Metastasis-directed therapy (MDT) involves direct local treatment of metastatic lesions through surgery or radiation, with the goal of killing all cancer cells in that location. Metastatic prostate cancer generally is treated with systemic therapies, the most common of which is continuous hormone therapy. Using MDT to treat patients with oligometastatic disease has increased in recent years.

Oligometastatic cancer, which is defined as five or fewer metastases seen on imaging, represents a transitional state between localized and widespread metastatic disease. The first study showing benefit with definitive local therapy was conducted at MD Anderson and published in 2016. Since then, there has been substantial research in this area.

However, despite data supporting the benefits of upfront hormone therapy and its synergy with radiation treatment, there have been no randomized trials testing this combination for patients with oligometastatic prostate cancer.

EXTEND is a Phase II randomized basket trial for multiple solid tumors testing whether the addition of MDT improves PFS for patients with oligometastatic cancer. PFS was prespecified to be independently assessed and reported at 41 progression events, which occurred after a median follow-up of 22.1 months.

The prostate cancer cohort randomized 87 men to receive either radiation plus intermittent hormone therapy or hormone therapy alone. Most participants (72 patients) were white, with seven Black patients, six Hispanic patients and two other patients included.

Hormone therapy consisted of a luteinizing hormone-releasing hormone agonist/antagonist with or without a second-generation androgen-receptor targeting agent. The benefits of MDT were preserved across patients regardless of whether they received a newer generation androgen-blocking agent. A planned hormone therapy break occurred six months after enrollment, and all men resumed hormone therapy at progression.

As a secondary endpoint, researchers also monitored the time that men could maintain normal testosterone levels while on their hormone therapy break. Adding MDT prolonged the time to progression; the median was not reached in the combination group, while the median time to progression was 6.1 months in men who received hormone therapy alone. These findings indicate that a strategy of radiation therapy and intermittent hormone therapy can maximize the time a man can safely maintain normal testosterone levels, which can preserve the patient's quality of life.

The treatment was well-tolerated, with three grade 3 toxicities observed in each arm. These consisted of impaired muscle motion as well as urinary and gastrointestinal side effects, but all were easily managed.

"This study shows that the combination of metastasis-directed radiation and intermittent hormone therapy significantly improved progression free-survival, with manageable toxicities, for patients with oligometastatic disease," Tang said. "I am encouraged that this data, combined with knowledge gained in future trials, will allow us to safely preserve a man's quality of life following this diagnosis."

The researchers also performed exploratory analyses on clinical samples, including flow cytometry and T-cell receptor sequencing, from peripheral blood at baseline and three months follow-up. Their data demonstrated increases in markers of T cell activation, proliferation and clonal expansion specifically in the combined therapy arm.

Additional research is needed to better understand these findings and to identify biomarkers to predict which men will benefit from this treatment combination. A large randomized trial is needed to directly compare continuous hormone therapy to scheduled breaks from the treatment.

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