Top Line: Immunotherapy is taking a swing at localized prostate cancer.
The Study: An intriguing phase 3 trial randomized patients receiving definitive external beam radiation with optional short-course ADT for intermediate (85%) or high (15%) risk prostate cancer to receive either placebo (n=249) or aglatimagene besadenovec (n=496), an intraprostatic gene therapy delivered via three ultrasound-guided injections. Aglatimagene is a replication-defective adenovirus carrying the herpes simplex virus thymidine kinase (HSV-tk) gene. After each injection, patients took 14 days of valacyclovir. Why? Apparently prostate cancer cells infected with HSV-tk convert valacyclovir into a toxic metabolite that selectively kills dividing cells, releasing a flood of prostate cancer antigens priming a systemic CD8+ T-cell response, while radiation simultaneously provides local tumor kill and additional antigen release. After a median follow-up of over 4 years, adding aglatimagene plus valacyclovir to definitive radiation reduced disease-free survival events from 31% to 23% (HR 0.70_ with more patients achieving a PSA nadir ≤0.2 ng/mL (67% vs 59%). Side effects with aglatimagene were mostly grade 1–2 flu-like symptoms after injection, while grade 3+ events were uncommon and similar between arms (8% vs 7%).
TBL: While it's too early to know whether this translates into fewer metastases or longer survival, the improved disease control and deeper PSA responses suggest aglatimagene may enhance the curative potential of radiation and possibly provide an avenue to de-escalate prolonged ADT. | DeWeese, Lancet Oncol 26
The Study: An intriguing phase 3 trial randomized patients receiving definitive external beam radiation with optional short-course ADT for intermediate (85%) or high (15%) risk prostate cancer to receive either placebo (n=249) or aglatimagene besadenovec (n=496), an intraprostatic gene therapy delivered via three ultrasound-guided injections. Aglatimagene is a replication-defective adenovirus carrying the herpes simplex virus thymidine kinase (HSV-tk) gene. After each injection, patients took 14 days of valacyclovir. Why? Apparently prostate cancer cells infected with HSV-tk convert valacyclovir into a toxic metabolite that selectively kills dividing cells, releasing a flood of prostate cancer antigens priming a systemic CD8+ T-cell response, while radiation simultaneously provides local tumor kill and additional antigen release. After a median follow-up of over 4 years, adding aglatimagene plus valacyclovir to definitive radiation reduced disease-free survival events from 31% to 23% (HR 0.70_ with more patients achieving a PSA nadir ≤0.2 ng/mL (67% vs 59%). Side effects with aglatimagene were mostly grade 1–2 flu-like symptoms after injection, while grade 3+ events were uncommon and similar between arms (8% vs 7%).
TBL: While it's too early to know whether this translates into fewer metastases or longer survival, the improved disease control and deeper PSA responses suggest aglatimagene may enhance the curative potential of radiation and possibly provide an avenue to de-escalate prolonged ADT. | DeWeese, Lancet Oncol 26