Formal discussant of the FORMULA-509 trial, Tyler Seibert, MD, PhD, of the University of California San Diego, commented: “The important take-away of these results is who benefited from the intensification arm. The overall cohort with a PSA [prostate-specific antigen] level up to 0.5 ng/mL did not, but the group with a PSA level higher than 0.5 ng/mL had a relevant and meaningful benefit in progression-free and metastasis-free survival. I also think it is interesting to consider that PSA > 0.5 ng/mL may be a surrogate for other biological features of aggressive disease that could be identified prior to the PSA rising above 0.5 ng/mL. Though hypothetical, it’s possible that subgroup would have done even better if they were treated earlier, before the PSA level began to rise, but we don’t know how to identify those patients.”

Dr. Seibert also noted that the subgroup with nodal metastasis, a clear marker of aggressive disease, did not benefit from intensification of therapy. “There was no benefit in the pN1 group. Perhaps the study was underpowered to detect this. However, if pN1 is not helpful to identify patients who will benefit from treatment escalation, then perhaps we need to reevaluate the value of pelvic lymph node dissection—and of the extent of pelvic lymph node dissection—in patients where postoperative radiation therapy is likely needed,” he continued.

Tyler Seibert, MD, PhD

“At present, the RADICALS-HD trial showed a strong benefit for 24 months of androgen-deprivation therapy in a study of more than 1,500 participants with a 10-year follow-up. However, intensification of radiation therapy for 6 months is a compelling concept for patients who are getting 6 months of androgen-deprivation therapy. Many patients would prefer to get 6 months of androgen-deprivation therapy and other therapies rather than 2 years of androgen-deprivation therapy because the duration of side effects will be less, and the overall impact on quality of life may be less,” he stated. 

“The other important consideration in this trial is that pelvic lymph node irradiation was not required. After FORMULA-509 was designed, another trial (RTOG 0534) demonstrated that irradiating the pelvic lymph nodes and adding 6 months of androgen-deprivation therapy (ADT) was superior to irradiating only the prostate fossa (without ADT). We rightly wonder what would have happened had pelvic lymph nodes been consistently treated with radiation therapy in ­FORMULA-509. Personally, given the relative effect sizes of pelvic radiation therapy and ADT in RTOG 0534, I would guess the effect of systemic therapy escalation in the subgroup with PSA > 0.5 ng/mL would remain even with radiation therapy to the pelvis.” 

DISCLOSURE: Dr. Seibert has received honoraria from Multimodal Imaging Services Corporation, Varian Medical Systems, and WebMD; and has served on the scientific advisory board of Cortechs Labs and has equity interest in the company; his instution has received in-kind research support from GE Healthcare.