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Bicalutamide in combination with Palbociclib for the treatment of AR+ metastatic breast cancer

Genome-wide transcriptional analysis has identified a unique subset of androgen receptor (AR)+, estrogen receptor ( ER ) / progesterone receptor (PR)- breast cancer.
The functional role of androgen receptor was confirmed initially in preclinical models demonstrating that androgen-driven growth could be abrogated by antiandrogen therapy.

TBCRC011 established the safety and efficacy of inhibiting androgen receptor with Bicalutamide ( Casodex ) in patients with AR+/ER/PR- metastatic breast cancer ( MBC ) with a median progression free survival ( PFS ) of 12 weeks ( 95% CI, 11–22 weeks ).

In preclinical data, Palbociclib ( Ibrance ) has been shown to reduce growth of AR+/ER/PR- MDA-MB-453 breast cancer cells. It has been shown that AR+ triple negative breast cancer ( TNBC ) expresses a luminal profile and has intact Rb protein, the target of Palbociclib activity.

Researchers have conducted a phase I/II trial of the AR inhibitor Bicalutamide in combination with the CDK4/6 inhibitor Palbociclib in patients with AR+/ER/PR/HER2- breast cancer to test the hypothesis that androgen blockade, paired with CDK4/6 inhibition would have increased efficacy in patients with androgen-dependent breast cancer.

Postmenopausal patients with AR+ TN MBC defined as IHC greater than or equal to 1% nuclear staining ( DAKO, Clone AR441 then Ventana AR SP107 ), ECOG less than or equal to 2, measurable / non-measurable disease were eligible for enrollment.

Any number of prior regimens was permitted.

Patients received Bicalutamide 150 mg daily and Palbociclib 125 mg daily 3 weeks on 1 week off. Patients were evaluated for toxicity every 2-4 weeks and for response every 8-12 weeks.

Primary endpoint was 6 month progression-free survival. Secondary endpoints were clinical benefit rate, toxicity, correlative studies to better characterize AR+ TNBC.
A Simon 2-stage minimax design that discriminates between 6 mo PFS rates of 20% and 40% was used. If greater than or equal to 11/33 patients were progression-free at 6 months then Bicalutamide + Palbociclib would warrant further study.

As of 1.1.20 33 patients were enrolled on study with median age 67 ( 42-79 ), performance status 0 ( 0-1 ).
Number of patients with visceral metastases was: 20; measurable disease: 22; AR% 1-9: 3, 10-50: 6; 51-100: 24.
Median prior lines for metastatic breast cancer: 3 ( 0-9 ).

Best response ( 31 evaluable patients ) was: 11 patients progression-free at 6 months: 10 stable disease ( SD ) more than 6 months, 1 partial response [ PR ].

Median weeks on study were: 14 ( 2-101 ).

The most common grade more than 3 adverse effects were: leukopenia: 21, neutropenia: 21, lymphocytopenia: 6, thrombocytopenia: 3; one patient with febrile neutropenia.

One death was due to disease progression within 30 days off study.

In conclusion, in this selected subset of patients with AR+ TN metastatic breast cancer, the study met its prespecified endpoint with 11 patients progression-free at 6 months on Bicalutamide 150 mg + Palbociclib 125 mg.
The combination of Bicalutamide and Palbociclib has been well tolerated with no unexpected toxicity observed. ( Xagena )

Source: American Society of Clinical Oncology ( ASCO ) Virtual Meeting, 2020