ARPI Doublet vs Triplet Therapy in Metastatic Prostate Cancer: Real‑World Survival and the Role of PSA Nadir

Therapy intensification in metastatic prostate cancer has expanded the repertoire of combination regimens, but it remains unclear which patients truly benefit from adding upfront docetaxel to an androgen receptor pathway inhibitor (ARPI) based doublet. A large real world cohort study using the U.S. based Patient360 Prostate dataset, which aggregates de identified electronic health records, linked claims, and mortality data, offers important insights into this question.
The study identified adults with prostate cancer initiating ARPI doublet (ARPI plus androgen deprivation therapy, ADT), docetaxel doublet (docetaxel plus ADT), or triplet (ARPI plus ADT plus docetaxel) and compared their baseline characteristics and survival outcomes. Among 10,347 patients with metastatic prostate cancer, ARPI doublet was by far the most common regimen, followed by triplet and docetaxel doublet, with a median age of 67 years and performance status largely preserved, given that 86.4% of patients had an ECOG score of 0 to 1.

Patients treated with docetaxel containing regimens tended to have more aggressive baseline features, including a higher prevalence of de novo metastatic disease, liver metastases, high grade histology (Gleason 8 to 10), and more frequent use of bone supportive agents. This suggests that clinicians were already reserving docetaxel intensified therapy for patients perceived as higher risk, which is crucial context when interpreting survival differences. Despite these imbalances, ARPI doublet was associated with considerably longer median overall survival from the start of therapy, 109 months, compared with 79 months for triplet and 64 months for docetaxel doublet. The survival advantage of ARPI doublet persisted even after multivariable adjustment, reinforcing that, on a population level, the two drug backbone remains the most commonly used and relatively favorable option in routine practice.

However, the story becomes more nuanced when PSA response is taken into account. A PSA nadir below 0.2 ng per mL emerged as a powerful prognostic marker: 42.9% of patients on ARPI doublet achieved this deep response, versus 29.1% and 30.2% on docetaxel doublet and triplet, respectively. Among those who did reach PSA nadir less than 0.2 ng per mL, median overall survival was extremely long, 202 months with ARPI doublet, 128 months with triplet, and 104 months with docetaxel doublet, indicating that patients who mount a profound biochemical response have a favorable trajectory regardless of regimen. In contrast, among patients who failed to reach PSA less than 0.2 ng per mL, median survival dropped substantially within each group (86, 71, and 59 months), and the differences between regimens were attenuated, suggesting that lack of deep PSA decline is a marker of intrinsically aggressive biology and poorer prognosis.

Multivariable analysis further underscored the importance of baseline disease characteristics, with de novo metastatic disease, liver metastases, baseline PSA above 200 ng per mL, and Gleason 8 to 10 independently associated with worse survival. These factors capture both tumor burden and tumor intrinsic aggressiveness and are consistent with prior real world evidence in metastatic prostate cancer.

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