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SAN ANTONIO -- Metastasis-directed radiotherapy (RT) significantly prolonged response to androgen deprivation therapy (ADT) in oligometastatic prostate cancer as compared with ADT alone, a small randomized trial showed.

Median progression-free survival (PFS) had yet to be reached with combined therapy after a median follow-up of 22.1 months, but the hazard for disease progression or death was reduced by 75% versus ADT alone, which led to a median PFS of 15.8 months. Metastasis-directed therapy also extended the duration of eugonadal PFS (testosterone >150 ng/dL) during a planned break from ADT, reducing the side effects of hormonal therapy.

"Metastasis-directed therapy combined with hormone therapy as part of an intermittent regimen improves PFS and thus time off from hormone therapy," said Chad Tang, MD, of the University of Texas MD Anderson Cancer Center in Houston, during a press briefing at the American Society for Radiation Oncology (ASTRO) annual meeting.

"Importantly for men, metastasis-directed therapy combined with hormone therapy also improves time with eugonad testosterone, something they all can enjoy," he added. "Intermittent hormone therapy in combination with metastasis-directed therapy may facilitate prolonged eugonad testosterone intervals while maintaining excellent disease control in men with this disease."

Multiple studies have shown that upfront (vs delayed) hormonal therapy improves overall survival in prostate cancer and has synergistic anticancer activity with RT. Hormone therapy also has well-known short- and long-term side effects, including changes in appearance, mood, sexual function, and musculoskeletal integrity.

"We know that men generally hate hormone therapy and that it's a big quality-of-life detriment to them," said Tang.

The SWOG S9346 trial in men with metastatic prostate cancer showed that was noninferior to continuous therapy, and planned drug holidays may reduce total exposure to anti-androgen therapy and its adverse effects. However, characteristics of the SWOG S9346 patient population might limit applicability of the findings to men with oligometastatic prostate cancer, Tang noted. The patients had a median prostate-specific antigen (PSA) value of 42 ng/dL at diagnosis, most of the patients had undetectable PSA levels after 7 months of ADT, and investigators had a high PSA threshold of ≥20 ng/dL for restarting ADT.

Acceptance and use of metastasis-directed therapy in oligometastatic prostate cancer have increased in recent years. However, use in combination with ADT had not been evaluated in a randomized trial.

Tang reported findings for prostate cancer from , a phase II randomized basket trial of add-on metastasis-directed therapy in various types of solid tumors. The prostate cancer part of the trial included 87 men with five or fewer metastases on hormone therapy for at least 2 months, who were randomized to continue hormone therapy alone (LHRH agonist/antagonist with or without a second-generation androgen receptor-targeting agent) or hormone therapy plus metastasis-directed RT.

A planned break in hormone therapy occurred after 6 months and continued until progression, defined as biochemical progression (≥2 ng/mL or ≥25% increase from nadir), clinical progression (symptoms or need to restart hormone therapy), or radiographic progression. The primary endpoint for the prostate cancer study was PFS, and the key secondary endpoint was eugonadal PFS.

The trial met the primary endpoint of PFS (95% CI 0.12-0.55, P<0.001). The addition of metastasis-directed therapy also significantly extended the time from eugonadal testosterone levels to disease progression (6.1 months with ADT vs not yet reached, P=0.025). A subgroup analysis showed that metastasis-directed therapy improved PFS in men who received a second-generation androgen receptor-targeting agent (HR 0.24, 95% CI 0.08-0.71) and those who did not (HR 0.36, 95% CI 0.15-0.83).

Grade 3 toxicity was limited to three cases in each treatment arm.

RT is one of several types of metastasis-directed therapies used to treat individual cancer lesions, said ASTRO president-elect Howard Sandler, MD, of Cedars-Sinai Medical Center in Los Angeles. Though he quibbled about the lack of details for the study's radiation therapy protocol, Sandler concluded, "However it was performed, it worked because the delay in time to progression is dramatic."

"Men who received relatively convenient, low-toxicity radiation to their metastatic sites were able to have extended time off of hormonal therapy," Sandler added. "As a prostate cancer-treating physician, I can tell you that this is clinically meaningful to patients. If we can extend their time off hormonal therapy with a eugonad testosterone level, basically having a normal testosterone level, receiving no therapy, then their quality of life is improved. Having taken care of many, many patients, mentally, these people are happier. So it's subjective improvement and quality of life."

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