vosilasarm (EP0062)

Adding the CDK4/6 inhibitor palbociclib enhanced the antitumor activity of EP0062 or fulvestrant in ESR1-mutant models but not in HER2-enriched or PTEN-mutant PDX models...EP0062 triggers an E2F1 downmodulation which mediates a potent antiproliferative activity. For EP0062-resistant tumors that remain ER-driven, the addition of palbociclib displays a potent antitumor effect.

P1/2, N=128, Recruiting, Ellipses Pharma | Not yet recruiting --> Recruiting

However, both a selective AR agonist (RAD140) and an AR inhibitor (enzalutamide, ENZ) have shown a therapeutic effect on ER+ breast cancer, so the potential for clinical application of AR-targeting therapy for ER+ breast cancer is still in dispute. In contrast, RAD140 activated AR signaling and suppressed AR-high tumor growth by deregulating ERα expression and blocking ERα function. Overall, analysis of the dynamic efficacies and outcomes of AR agonist and antagonist in the presence of different AR and ERα levels reveals regulators of response and supports the clinical investigation of ENZ in selected ER+ tumors with a low AR/ER ratio and AR agonists in tumors with a high AR/ER ratio.

P1/2, N=128, Not yet recruiting, Ellipses Pharma

Clinic follow-up will be at 2 and 4 weeks, then every 4 weeks until disease progression. Recruitment is scheduled to initiate in Q4 2022.

In vivo antitumor activity of RAD140 alone or in combination with palbociclib was tested in comparison to fulvestrant plus palbociclib. Conclusion RAD140 exhibits antitumor activity in hormone-independent and ESR1 -altered ER+/HER2- PDX models as single agent or in combination with CDK4/6i. Mechanistically, AR agonists decrease proliferation as shown by a decrease in Ki67 and S/G2-cell cycle cyclin levels.

RAD140 is a novel oral AR-targeted agent for the treatment of AR+/ER+/HER2- mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity.

RAD140 and enzalutamide are compelling candidates for monotherapy or combination with anti-estrogen therapies in ER+/AR+ breast cancer. Future clinical validation of the models and therapeutic effect is warranted.

RAD140 (3 mg/kg twice daily), elacestrant (30 mg/kg once daily), and palbociclib (10 mg/kg once daily) were administered via oral gavage for the duration of study...The selective ER degrader (SERD) fulvestrant had TGI of 7%, while the oral SERD elacestrant (RAD1901) had TGI of 60%...The AR antagonist apalutamide was found to partially reverse the apoptosis induced by RAD140 and DHT, further supporting the on-target effect... Our data suggest the anti-tumor activity of RAD140 may be mediated through suppression of ER signaling as well as additional mechanisms. The effect of RAD140 on DNA damage and apoptosis implies the potential for combination therapy with agents targeting cell survival and DNA damage repair pathways. RAD140 is being studied in a Phase 1, first-in-human trial in postmenopausal women with hormone receptor positive BC (NCT03088527).

Median number of prior lines of therapy for mBC = 4; prior fulvestrant 86%, aromatase inhibitor 96%, CDK4/6i 91%, mTORi/PI3Ki 46%, chemotherapy 91%. The MTD and recommended dose for RAD140 is 100 mg QD. RAD140 is a novel oral AR-targeted agent for the treatment of AR+/ER+ mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity. This study is ongoing.