Treatment approaches for metastatic hormone-sensitive prostate cancer (mHSPC) are rapidly evolving, leading to ongoing discussions among clinicians regarding the efficacy of triplet versus doublet therapy. The debate centers on whether intensifying treatment with a triplet approach—androgen deprivation therapy (ADT), androgen receptor pathway inhibitors (ARPIs), and docetaxel—should be the standard of care for all patients, or if doublet therapy remains a viable option for specific subgroups.
The Case for Triplet Therapy
Bassel Nazha, MD, MPH, an assistant professor at Emory University School of Medicine, argues that triplet therapy is the most effective approach for mHSPC. He emphasized that the addition of docetaxel to ADT and ARPIs improves survival through treatment intensification, a multitargeted strategy, and comprehensive disease control. "Importantly, a triplet therapy approach targets early disease resistance through nonoverlapping mechanisms," Nazha stated.
The landmark phase 3 PEACE-1 trial (NCT01957436) evaluated the addition of abiraterone acetate (Zytiga) with or without local radiation to standard of care (SOC). At the time, SOC was ADT monotherapy, but the protocol was amended to allow for docetaxel use. The results demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS). As a comparison, the OS for the CHAARTED trial (NCT00309985), evaluating ADT plus docetaxel, was 58 months, and the OS for the LATITUDE trial (NCT01715285), evaluating ADT plus abiraterone, was 50 months.
The ARASENS trial (NCT02799602) also showed a benefit associated with triplet therapy, with the median OS not reached. This benefit was consistent across prespecified subgroups. According to Nazha, this level 1 evidence for OS benefit from PEACE-1 and ARASENS demonstrates the superiority of triplet therapy over doublet therapy. "For fit patients with hormone-sensitive prostate cancer, I believe it is most viable to give the most effective therapy first, and that is triplet therapy," Nazha concluded.
The Case for Doublet Therapy
Jordan Ciuro, MD, an assistant professor at the Medical College of Georgia, contends that "there is still a continued role for doublet therapy in metastatic castrate-sensitive disease." She highlighted the inherent heterogeneity of prostate cancer, arguing that "no single treatment modality should apply to all patients." Ciuro noted the existence of various subtypes within this disease, such as high-volume disease based on the CHAARTED data and high-risk disease based on the LATITUDE trial.
Ciuro pointed out that the PEACE-1 trial included patients with de novo mHSPC, a particularly aggressive form of the disease. She also reviewed the baseline characteristics, noting that patients in PEACE-1 were generally younger, with no one older than 70 years; visceral involvement was observed in 12% to 13% in each arm; and over 60% had high disease burden. In patients who received ADT plus docetaxel with low-volume metastatic burden, the HR was 0.83 (95% CI, 0.50-1.39; P = .66). In patients treated with ADT with docetaxel in patients with high-volume metastatic burden, the HR was 0.72 (95% CI, 0.55-0.95; P = .019).
Evaluating the ARASENS trial, Ciuro noted that the patient demographics indicated a younger patient population who were fit but also had high-volume disease (77%) and high-risk disease (70%).
Ciuro concluded, "We truly need a trial evaluating the benefit of chemotherapy added to doublet therapy, that is, chemotherapy plus an APRI and ADT vs placebo plus an APRI and ADT. We do not have that data at the moment." She questioned whether triplet therapy should be the new SOC for all patients with mHSPC, stating, "Right now, I would say no, although there is utility for this treatment intensification but we need to tailor it for the right patient cohort."
