Randomized Crossover Ph3 to Evaluate Efficacy/Safety of Enobosarm Monotherapy vs Active Control for Treatment of AR+/ER+/HER2- MBC With AR Staining Previously Treated w/Nonsteroidal Aromatase Inhibitor, SERD & CDK 4/6 Inhibitor

• Provide informed consent

• Be able to communicate effectively with the study personnel

• Aged ≥18 years

• For Female Subjects

‣ Menopausal status

• Be postmenopausal as defined by the National Comprehensive Cancer Network as either:

‣ Age ≥55 years and one year or more of amenorrhea

⁃ Age \<55 years and one year or more of amenorrhea, with an estradiol assay \<20 pg/mL

⁃ Age \<55 years and surgical menopause with bilateral oophorectomy

• Be premenopausal or perimenopausal on ovarian suppression with LHRH agonist for at least 4 months, with an estradiol assay \<20 pg/mL and a negative urine pregnancy test.

• If subject is of child bearing potential, the subject must agree to use acceptable methods of contraception:

‣ If female study participant could become pregnant, use acceptable methods of contraception from the time of the first administration of study medication until 6 months following administration of the last dose of study medication. Acceptable methods of contraception are as follows: Condom with spermicidal foam/gel/film/cream/suppository \[i.e., barrier method of contraception\], surgical sterilization of male partner (vasectomy with documentation of azoospermia) and a barrier method {condom used with spermicidal foam/gel/film/cream/suppository}

⁃ If female study participant has undergone documented tubal ligation (female sterilization), a barrier method (condom used with spermicidal foam/gel/film/cream/suppository) should also be used

⁃ If female study participant has undergone documented placement of an intrauterine device (IUD) or intrauterine system (IUS), a barrier method (condom with spermicidal foam/gel/film/cream/suppository) should also be used

• For Male Subjects

‣ Subject must agree to use acceptable methods of contraception:

• If the study subject's partner could become pregnant, use acceptable methods of contraception from the time of the first administration of study medication until 6 months following administration of the last dose of study medication. Acceptable methods of contraception are as follows: Condom with spermicidal foam/gel/ film/cream/suppository \[i.e., barrier method of contraception\], surgical sterilization (vasectomy with documentation of azoospermia) and a barrier method {condom used with spermicidal foam/gel/film/cream/suppository}, the female partner uses oral contraceptives (combination estrogen/progesterone pills), injectable progesterone or subdermal implants and a barrier method (condom used with spermicidal foam/gel/film/cream/suppository)

• If female partner of a study subject has undergone documented tubal ligation (female sterilization), a barrier method (condom used with spermicidal foam/gel/film/cream/suppository) should also be used

• If female partner of a study subject has undergone documented placement of an intrauterine device (IUD) or intrauterine system (IUS), a barrier method (condom with spermicidal foam/gel/film/cream/suppository) should also be used

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤2

• Documented evidence of ER+/HER2- metastatic breast cancer

• Measurable disease is required as per RECIST 1.1 (NOTE: Bone only metastatic disease is acceptable but requires a measurable component

• Have androgen receptor nuclei staining ≥40% as assessed by central laboratory

• Received at least 2 prior lines of treatment in MBC setting which must have included both an AI (monotherapy or combination) and fulvestrant (monotherapy or combination); at least one must have been given in combination with a CDK 4/6 inhibitor.

• Previously responded (without disease progression for at least 6 months) to one of the following treatments: fulvestrant monotherapy or fulvestrant plus CDK 4/6 inhibitor or nonsteroidal aromatase inhibitor monotherapy or nonsteroidal aromatase inhibitor plus CDK 4/6 inhibitor for metastatic breast cancer.

• Subject is willing to comply with the requirements of the protocol through the end of the study