Importantly, when corrected for species equivalency by body surface area, BZA and PIP were administered at doses similar to those previously evaluated in the clinic. Due to the high number of experimental Pyridoxine groups, the data are presented in several panels to facilitate relevant comparisons.In this wellvalidated model of tamoxifenresistant breast cancer, we noted that palbociclib, BZA, PIP, and ICI, when evaluated as monotherapies, were similarly effective at inhibiting tumor growth. The inhibition of tumor growth was similar in animals treated with mgkg BZA or PIP as compared with mgkg. Interestingly, tumor regression was initially observed for palbociclib treatment, followed by robust resistance in a subset of animals after to weeks of treatment. The mechanism by which these tumors develop resistance to palbociclib is currently under investigation.Consistent with our in vitro analyses, it was observed that all of these compounds reduced the levels of intratumoral ESR, whereas palbociclib Choline chloride treatment had no signicant effect on receptor expression. Because palbociclib had not previously been evaluated in PDX models, we initially assessed the efcacy of palbociclib treatment alone in tumors expressing wildtype, or expressing the ESRDG mutation. Tam control and palbociclib only treatments presented on each graph are identical.Having demonstrated the activity of palbociclib as a monotherapy in these clinically relevant models, we next evaluated its activity when administered in combination with BZA.In this model, it was observed that BZA, palbociclib, or the combination were similarly effective in blocking tumor growth. The enduring presence of tamoxifen and aromatase inhibitors in contemporary breast cancer treatment regimens attests to the central importance of ESR as a driver of tumor growth and progression.However, resistance to endocrine therapy is nearly universal in advanced disease, and ESR tumors remain the majority cause of death from breast cancer.Although the mechanisms underlying resistance to endocrine therapy are complex and varied, loss of dependence on ESR and its downstream signaling pathways is an infrequent event.Therefore, ESR and the estrogen signaling axis remain important therapeutic targets, an observation that has driven the search for agents that target this pathway by new mechanisms.In this study, we demonstrate that ICI, BZA, and PIP, highafnity competitive antagonists of ESR that downregulate the receptor to varying degrees, are effective in relevant models of endocrine therapyresistant disease.Importantly, these modulators inhibited the activity of clinically relevant ESR mutations with efcacy similar to that observed for the WT ESR despite signicantly reduced potency.Most importantly, we observed in both endocrineresistant breast cancer xenograft tumors, and in PDX tumors expressing a relevant mutation of ESR, that the SSHSERD BZA in combination with palbociclib resulted in signicant tumor growth control.It is generally accepted that suboptimal pharmaceutical properties of the only currently approved SERD, fulvestrant, limit the achievable tumor exposure. Despite these difculties, higher doses of fulvestrant have improved overall survival in two trials, highlighting the promise of more effective ESR targeting.Fortunately, most of the newer, thirdgeneration ESR antagonists have improved pharmaceutical properties and their efcacy should not be limited by drug exposure.However, BZA, a lowtoxicity drug that has already been approved for the treatment and prevention of osteoporosis, may have immediate utility in advanced disease.