In a column for OncLive, Garmezy argues that androgen deprivation therapy combined with an androgen receptor pathway inhibitor provides an appropriate foundation for many patients with metastatic hormone-sensitive prostate cancer, but deciding which patients should receive a third agent requires weighing molecular findings, anticipated benefit, and treatment-related toxicity.
ADT Plus an ARPI Forms the Backbone of Care
Garmezy identifies the combination of ADT and an androgen receptor pathway inhibitor (ARPI) as the baseline for many patients, and that view aligns with how treatment patterns have shifted globally. In a UroToday discussion, Gerhardt Attard of University College London noted that roughly half of metastatic patients in the U.S., Germany, and France received ADT monotherapy over an eight-year period, though he said a higher proportion are now being offered intensification with an ARPI, and a subset receive triple therapy adding docetaxel. Attard attributed the initial evidence for that shift to the STAMPEDE and LATITUDE trials presented in 2017.
BRCA1/2 Mutations Point Toward PARP Inhibitors
Garmezy highlighted BRCA1/2 mutations as important considerations when evaluating PARP inhibitor–based intensification, according to OncLive. He noted that questions remain about extending these approaches to patients with other molecular alterations, particularly when balancing efficacy against additional adverse effects. PTEN loss and PSMA expression introduce further considerations for targeted treatment selection, he said.
When biomarkers overlap, those decisions become harder to navigate: one patient might carry a BRCA1 mutation, PTEN loss, and PSMA-positive disease, which opens up several possible routes for intensification while leaving the best approach unresolved, Garmezy explained.
Docetaxel Remains an Established Option
Garmezy also highlights docetaxel as a proven treatment option still used today as chemotherapy options grow. That relevance shows up in real-world patterns: Attard told UroToday that in the U.K., the big change came around COVID, when use of docetaxel dropped sharply and was primarily replaced by ARPIs, mostly because of funding access.
Global Patterns Show Uneven Adoption of Intensification
Attard and Nicholas James also pointed to wide geographic variation in first-line treatment. They noted very high use of first-generation ARPIs such as bicalutamide in Japan and China, where urologists believe those drugs behave differently in their populations than in European groups. Attard added that abiraterone shows higher toxicity in China, and James recalled being repeatedly asked in Japan how clinicians manage enzalutamide’s severe toxicity — a reaction he attributed partly to lower average BMI and effectively higher doses per kilogram.
Shared Decision-Making Weighs Quality of Life
Garmezy stressed that shared decision-making should take into account comorbidities, what the patient prefers, and which toxicities that person is prepared to tolerate. Preserving quality of life is particularly important when patients are feeling well early in their disease course, he said. He finished by saying that teamwork between urologists and genitourinary medical oncologists is crucial as therapies continue to change, though the best ways to select among them remain unresolved, and doctors ought to inform patients about the available options and bring them actively into the treatment conversation.
Open Questions in mHSPC Treatment Selection
Which patients should receive a third agent? Garmezy says the decision requires considering molecular findings, anticipated benefit, and toxicity, with BRCA1/2 mutations a key marker for PARP inhibitor–based intensification. What happens when biomarkers overlap? A patient with BRCA1 mutation, PTEN loss, and PSMA-positive disease faces several intensification avenues with no established optimal sequence. Attard reports that about half of metastatic patients in major Western countries historically received ADT alone, while U.K. docetaxel use fell during COVID and was replaced largely by ARPIs.
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