Sequence of ADT With Radiation Is Crucial for Prostate Cancer Treatment

Daniel Spratt, MD

The sequence in which hormonal therapy is given to men with localized prostate cancer should be considered as it can significantly affect outcomes, according to pooled data from 2 phase 3 clinical trials.

A team of researchers led by Daniel Spratt, MD, a professor of radiation oncology at the University of Michigan, conducted a systematic literature search using MEDLINE, Embase, trial registries, and major urology and oncology conference proceedings to retrieve studies that evaluated the optimal sequencing of definitive radiation therapy (RT) with androgen deprivation therapy (ADT) in men with localized prostate cancer.

Patient data were collected after their search was narrowed to 2 studies—the NRG Oncology’s Radiation Therapy Oncology Group (RTOG) 9413 trial (Protocol) and the randomized Ottawa 0101 trial. In the latter trial, patients were randomly assigned to neoadjuvant or concurrent vs concurrent or adjuvant short-term ADT. RTOG 9413 included a random assignment of neoadjuvant or concurrent vs adjuvant short-term ADT.

“In almost all cancer types when giving radiation or surgery, the timing of systemic therapy has been directly assessed. In some cancer types, concurrent systemic therapy with radiotherapy has been shown to be superior to sequential therapy,” explained Spratt in an interview with OncLive^®. “However, in prostate cancer, of the dozens of randomized phase 3 trials assessing the role of ADT, almost none of the trials have assessed sequencing of RT and ADT, but rather duration and use of ADT with RT. Furthermore, many of the trials use different durations and sequences of ADT with RT. For example, some have used purely neoadjuvant ADT (before RT), purely adjuvant ADT (after RT), or combinations of neoadjuvant, concurrent, and adjuvant ADT ranging from 3 months to 3 years. Thus, we wanted to determine if underlying all the results we have seen on trials of ADT and RT there was a missing factor, the optimal sequencing of RT and ADT.”

The primary endpoint was progression-free survival (PFS), and secondary endpoints included metastasis-free survival (MFS) and overall survival (OS).

Data from more than 1000 patients (531 neoadjuvant and 534 adjuvant) were examined. The median age was 70 years, 58.1% had a Gleason score of 7 and 16.9% had a Gleason score of 8 to 10. Nearly 20% of patients had clinical T3 and T4 disease, and the median prostate-specific antigen (PSA) was 14.1 ng/mL.

At a median follow-up of 14.9 years, PFS was significantly improved in the adjuvant group compared with the neoadjuvant group at 36% vs 29%, respectively (HR, 1.25; 95% CI, 1.07-1.47; P = .01.). In addition, biochemical failure, distant metastasis, and MFS were all significantly improved as well.

Investigators observed no significant difference in OS, at 15-year rates of 34% vs 39% for the neoadjuvant and adjuvant groups, respectively. The HR for the neoadjuvant group was 1.11 HR for the neoadjuvant group, 1.11 [95% CI, 0.95-1.30; P = .20).

Similarly, there were no significant differences in late grade 3 to 5 gastrointestinal (2% vs 3%, P = .33) or genitourinary (5% vs 5%, P = .76) toxicities between the 2 groups.

The study results also suggested that patients had a lower risk of dying from prostate cancer. However, this finding was not statistically significant, investigators noted.

“Prior preclinical work from my laboratory showed that RT causes upregulation of the androgen receptor, which in turn upregulates DNA repair genes to repair the RT-induced DNA damage,” said Spratt. “This upregulation lasts for weeks if not months after RT, and thus have hypothesized for years that adjuvant ADT may be the most critical component to therapy. We have known for years that ADT slows proliferation of cancer cells, which may in fact make them more radioresistant. This has always been a concern regarding neoadjuvant ADT. However, some have hypothesized that neoadjuvant ADT might be of benefit given it has been shown to reduce tumor hypoxia.”

Spratt and his team are now finalizing their mechanistic preclinical work, which further validates the clinical findings. For oncologists, he expressed that adjuvant ADT is a critically important component of prostate cancer treatment when combining ADT and RT.

“It is unclear that neoadjuvant ADT has any oncologic benefit but may be used for cytoreduction in locally advanced cases or very large prostates, or to rapidly stop the progression of disease in patients with rapidly growing tumors,” said Spratt. “However, adjuvant ADT should still be given. In our study the benefit of adjuvant ADT compared with neoadjuvant ADT was similar in fact to the benefit of even giving short-term ADT vs no ADT in trials like RTOG 9408.”

Reference

1. Spratt DE, Malone S, Roy S, et al. Prostate radiotherapy with adjuvant androgen deprivation therapy (ADT) improves metastasis-free survival compared to neoadjuvant ADT: an individual patient meta-analysis. J Clin Oncol. Published online December 4, 2020. doi:10.1200/JCO.20.02438