Endoxifen Shows Promise in Breast Cancer

With more than 40 years of clinical history, the selective estrogen receptor modulator tamoxifen is a leading therapy for estrogen receptor (ER)–positive breast cancer. However, most women eventually develop resistance to it, and many die of their disease. As a prodrug, tamoxifen relies on the activity of its metabolites for clinical effects.

Investigators have tried for decades to identify a more efficacious alternative, and recent efforts have focused on a tamoxifen metabolite, endoxifen, whose affinity for ER far exceeds that of its parent compound.

Now phase I findings indicate that endoxifen is both well tolerated and antitumorigenic, suggesting promise for the treatment of ER-positive breast cancer. “Many patients who take tamoxifen wind up with endoxifen concentrations that are too low,” says principal investigator Matthew Goetz, MD, professor of oncology at the Mayo Clinic in Rochester, MN, who presented the findings last month at the 2013 San Antonio Breast Cancer Symposium in Texas. “We administered endoxifen directly and found that we could achieve substantial concentrations in plasma without incurring any new safety problems.”

During the study, 22 women with metastatic, aromatase inhibitor–refractory, ER-positive breast cancer took endoxifen once daily at doses ranging from 20 mg to 160 mg. Steady state plasma concentrations increased proportionately with the dose, achieving endoxifen levels that researchers say cannot be reached with tamoxifen. The most common side effect was hot flashes, and a maximum tolerated dose was not identified.

“For patients with measurable disease, 10 of 14 (71%) had either stable disease or tumor shrinkage as their best response,” Goetz notes. “This degree of antitumor activity was exciting, given that all patients on this study had failed aromatase inhibitors, and many had failed fulvestrant and tamoxifen.”

Tamoxifen is metabolized to endoxifen by the enzyme CYP2D6. It's long been thought that low CYP2D6 activity explains the low endoxifen levels among some women who take tamoxifen. Indeed, says Goetz, endoxifen was initially developed for “slow CYP2D6 metabolizers.” But experts disagree over whether differences in enzymatic activity of genetic variants of CYP2D6 correlate with differences in tamoxifen efficacy.

“My feeling is that women with and without the variant enzyme will respond similarly to tamoxifen,” says C. Kent Osborne, MD, professor of medicine and cell biology at Baylor College of Medicine in Houston, TX, who was not involved in the study. “It's also possible that endoxifen is the better drug regardless of CYP2D6 status, given that it's the most potent tamoxifen metabolite in terms of ER binding.”

According to Goetz, researchers plan to launch a phase II trial in 2014 comparing endoxifen with tamoxifen, also in women with metastatic breast cancer refractory to aromatase inhibitors. “Ultimately we need to compare endoxifen head to head with tamoxifen,” he says, “but so far, our experience with endoxifen is quite encouraging.”