Dr Antonarakis on Early Intervention With PARP Inhibitors in mHSPC

Emmanuel Antonarakis, MD, associate director, Translational Research, Masonic Cancer Center, the Clark Endowed Professor of Medicine, University of Minnesota Medical School, discusses current clinical trials investigating the use of PARP inhibitors that may push the boundaries of the treatment paradigm for metastatic prostate cancer, including studies shifting treatments toward earlier stages of the disease, specifically targeting the hormone-sensitive phase.

Antonarakis highlights clinical trials such as the phase 3 AMPLITUDE (NCT04497844), TALAPRO-3 (NCT04821622), and EvoPAR-PR01 (NCT06120491) trials, which are investigating the efficacy of PARP inhibitors combined with androgen deprivation therapy (ADT) in this setting.

AMPLITUDE explored the use of niraparib (Zejula) in combination with abiraterone acetate (Zytiga) and prednisone vs abiraterone plus prednisone and placebo in patients with newly diagnosed, metastatic hormone-sensitive prostate cancer (mHSPC) deleterious germline or somatic harboring homologous recombination repair (HRR) gene mutations. This trial aims to determine whether initiating PARP inhibition at this early stage, rather than waiting until castration resistance develops, improves outcomes, Antonarakis explains.

TALAPRO-3 is comparing the combination talazoparib (Talzenna) plus enzalutamide (Xtandi) and ADT versus Enzalutamide plus placebo in patients with mHSPC with DNA damage response (DDR) alterations. Previously, in June 2023, the FDA approved talazoparib plus enzalutamide for use in patients with HRR gene–mutated metastatic castration-resistant prostate cancer (mCRPC), based on data from the phase 3 TALAPRO-2 trial (NCT03395197). TALAPRO-3 is aiming to ascertain the benefit of adding a PARP inhibitor in the first-line treatment regimen for patients with mHSPC, Antonarakis notes.

EvoPAR-PR01, which is still recruiting patients, is evaluating saruparib (AZD5305) in combination with physician’s choice of hormonal therapy—abiraterone acetate, enzalutamide, or darolutamide (Nubeqa)—vs physician’s choice of hormonal therapy plus placebo in patients with mHSPC. The study will include two cohorts of patients: those with and without HRR gene mutations.

These trials address the question of whether incorporating PARP inhibitors earlier in the treatment paradigm for mHSPC, particularly in patients with specific biomarkers such as HRR gene mutations or BRCA1/2 mutations, offers superior outcomes compared to delaying PARP inhibition until castration resistance occurs, Antonarakis explains.

By targeting the hormone-sensitive phase of metastatic prostate cancer, these trials aim to optimize treatment strategies and potentially delay disease progression. The results of these studies will provide valuable insights into the role of PARP inhibitors in combination with standard therapies in the management of metastatic prostate cancer and may influence future treatment guidelines, he concludes.