Molecular apocrine breast cancer (MABC) accounts for ~10% of breast cancer diagnoses and is associated with poor prognosis. This molecular subtype is defined as negative for the female sex hormone receptors estrogen (ER) and progesterone (PR) and positive for the male sex hormone receptor androgen (AR); with the HER2 oncogene amplified or mutated in most cases. In MABC, the high levels of AR have been misconceived in a proliferative role, a concept that has become paradigmatic and has led to several clinical trials involving AR antagonists. Clinical trialling of the AR antagonist bicalutamide, however, resulted in a limited benefit (19%) for ER-AR+ patients. Given the efficacy of AR agonism in ER-positive breast cancer, we hypothesised that AR agonists rather than antagonists could effectively treat MABC. To test this, we used a potent AR agonist (5a-dihydrotestosterone – DHT) and a contemporary competitive AR antagonist (enzalutamide), alone or in combination, to treat clinically relevant patient-derived xenograft (PDX) models of MABC (ER-AR+HER2Amp). In our models (CTPx3921, HCI-012), AR antagonism with enzalutamide as a single agent had no effect on basal growth. In contrast, treatment with DHT potently inhibited growth of CTPx3921 tumours, but had no significant effect on HCI-012. The growth inhibition exerted by DHT in CTPx3921 was attenuated by co-treatment with enzalutamide, endorsing its anti-androgenic activity in vivo. Genomic analyses are being undertaken with the PDX tumours and relevant cell lines. In summary, we provide compelling evidence that not all MABCs will benefit from an AR antagonist therapy, contradicting the existing paradigm of AR-driven growth in this subtype. Moreover, we demonstrate that some MABC tumours will respond to AR agonist therapy. Our results could explain the limited benefit reported in the clinical trial using bicalutamide in ER-AR+ metastatic breast cancer. Future analysis will be critical to explain the efficacy of AR agonism in MABC and will provide the essential basis to design new therapeutic strategies for this aggressive subtype of breast cancer.