Prior local therapy does not impact mCRPC survival with ARPI treatment

Omar Azem, MD

Credit: Rush University

The treatment effects of first-line androgen receptor pathway inhibitors (ARPIs) are not significantly compromised due to prior local therapy among patients with metastatic castrate resistant prostate cancer (mCRPC), according to new meta-analysis data.

A pooled analysis of the COU-AA-302 and ACIS clinical trials—presented in a late-breaking abstract session at the American Society for Radiation Oncology (ASTRO) 2024 Annual Meeting in Washington, DC, this weekend—showed that prior local therapy modalities did not significantly impact the effect of ARPIs, nor did it correlate with any increased risk of radiographic progression or deaths in patients with mCRPC.

The data, presented by study author Omar Azem, MD, a fourth-year radiation oncology resident with Rush University, may provide oncologists more prescribing confidence with targeted therapies for patients with mCRPC regardless of their prior local therapy exposure.

“Pre-clinical studies suggest that prior local therapy could portend neuroendocrine differentiation and could result in compromised response to subsequent lines of systemic therapy including androgen deprivation therapy (ADT) or ARPI,” Azem and colleagues wrote. “In contrary, clinical studies show conflicting findings in this domain.”

Investigators sought to observe the potential modifying effect local therapy may have on first line treatment’s effect on overall survival, as well as whether local therapy was independently associated with overall and radiographic progression free survival (rPFS) among patients with mCRPC. The team analyzed data from the cohorts of the COU-AA-302 and ACIS trials to define these potential associations.

The COU-AA-302 trial, originally published in January 2013, showed androgen biosynthesis inhibitor abiraterone acetate (Zytiga) plus twice-daily prednisone provided a 47% improved rPFS relative to lone prednisone in chemotherapy-naïve patients with mRCPC. In ACIS, published in 2021, the addition of ARPI apalutamide (ERLEADA) to combination abiraterone – prednisone resulted in a 31% reduced risk of rPFS or death versus abiraterone – prednisone in patients with mCRPC naïve to chemotherapy.

Azem and colleagues conducted a meta-analysis of individual patient data from these 2 trials to interpret the role of prior local therapy on outcomes with ARPIs and ADT. Difference in treatment effect on overall survival among the cohorts, stratified by prior local therapy exposure, was defined via hierarchical multivariable Bayesian Coz proportional hazard regression models. Association between prior local therapy exposure and rPFS as well as overall survival was defined through an independent analysis.

The final analysis included 2032 patients, stratified by trial treatment arms as follows:

• Lone ADT (n = 527), of whom 339 (64.3%) received prior local therapy.
• ADT plus abiraterone (n = 1020), of whom 559 (54.8%) received prior local therapy.
• Apalutamide plus abiraterone (n = 485), of whom 234 (48.3%) received prior local therapy.

Among the 1132 patients to receive prior local therapy, 534 (47.1%) had radiotherapy (RT), 253 (22.3%) had radical prostatectomy (RP), and 345 (30.5%) had RP plus RT.

Investigators observed no significant difference in the effect of prior local therapy on overall survival when comparing patients who received lone ADT (hazard ratio [HR], 0.90; 95% CI, 0.69 – 1.17) or apalutamide plus abiraterone (HR, 1.29; 95% CI, 0.99 – 1.69) when compared with ADT plus abiraterone.

Local therapy modality was additionally not significantly associated with rPFS outcomes in ADT or ARPI-treated patients:

• RP (HR, 0.98; 95% CI, 0.81 – 1.18)
• RT (HR, 0.99; 95% CI, 0.86 – 1.16)
• RP plus RT (HR, 1.03; 95% CI, 1.03)

Associations between local therapy modalities and overall survival with ADT or ARPIs were similarly insignificant among patients with mCRPC.

“In this meta-analysis, we did not find any significantly compromised treatment effects from first line ARPI in patients who received prior local therapy,” investigators wrote. “Further, there was no significant association of prior local therapy modality with risk of radiographic progression or deaths, respectively.”

References

1. ^{Azem OM, Roy S, Sun Y, Cueto-Marquez AE, et al. Impact of Prior Local Therapy (LT) on Treatment Response and Survival of Men with Metastatic Castrate Resistant Prostate Cancer (mCRPC): A Pooled Analysis of COU-AA-302 and ACIS Trials. Poster presented at: American Society for Radiation Oncology (ASTRO) 2024 Annual Meeting. Washington, DC. September 29 – October 2, 2024.}
2. ^{Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy [published correction appears in N Engl J Med. 2013 Feb 7;368(6):584]. N Engl J Med. 2013;368(2):138-148. doi:10.1056/NEJMoa1209096}
3. ^{Saad F, Efstathiou E, Attard G, et al. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2021;22(11):1541-1559. doi:10.1016/S1470-2045(21)00402-2}