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

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

At a median follow-up of 22.1 months, median PFS had not yet been reached in men receiving combination therapy, indicating a significant improvement over the median PFS of 15.8 months in men receiving hormone therapy alone. The combination was well tolerated and extended the length of time men could maintain a break from hormone therapy without progression, suggesting that this approach could improve the quality of life of men with advanced prostate cancer.

We know that radiation technology has evolved to directly target metastases, reduce side effects, and 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, MD, Phprincipal investigator, Adocent for radiation oncology

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

Oligometastatic carcinoma, which is defined as five or fewer metastases seen on imaging, represents an intermediate state between localized and widespread metastatic disease. The first study demonstrating the benefit of definitive topical therapy was conducted at MD Anderson and published in 2016. Since then, there has been considerable research in this area.

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

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

In the prostate cancer cohort, 87 men were randomized to receive either radiation plus intermittent hormone therapy or hormone therapy alone. The majority of participants (72 patients) were white, including seven black patients, six Hispanic patients, and two other patients.

Hormonal 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 maintained in patients regardless of whether they received a newer generation androgen blocker. A planned break in hormone therapy occurred six months after enrollment, and all men resumed hormone therapy at progression.

As a secondary endpoint, the researchers also looked at how long the men could maintain normal testosterone levels while off hormone therapy. Addition of MDT increased time to progression; the median was not reached in the combination group, while the median time to progression was 6.1 months in men receiving hormone therapy alone. These findings suggest that a strategy of radiation therapy and intermittent hormone therapy may maximize the length of time a man can safely maintain normal testosterone levels, which may 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 movement as well as urinary and gastrointestinal side effects, but all were easily managed.

“This study shows that the combination of metastasis-targeted radiation and intermittent hormone therapy significantly improved progression-free survival with manageable toxicity in patients with oligometastatic disease,” Tang said. “I am encouraged that these data, combined with the knowledge gained in future studies, will allow us to safely preserve a man’s quality of life after this diagnosis.”

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

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