In addition, AR signaling inhibits thymocyte production [31], whereas AR blockade has been shown to increase naive T cell generation resulting in a larger diversity of T cell repertoire that could potentially respond to PD\1 blockade [32, 33]. pembrolizumab 200 mg intravenous (IV) every 3?weeks and enobosarm 18 mg oral daily. The primary objective was to evaluate the security of enobosarm plus pembrolizumab and determine the response rate. Peripheral blood, tumor biopsies, and stool samples were collected for correlative analysis. Results The LY 344864 hydrochloride trial was halted early because of the withdrawal of GTx\024 drug supply. Eighteen patients were enrolled, and 16 were evaluable for responses. Median age was 64 LY 344864 hydrochloride (range 36C81) years. The combination was well tolerated, with only a few grade 3 adverse events: one dry skin, one diarrhea, and one musculoskeletal ache. The responses were 1 of 16 (6%) total response (CR), 1 of 16 (6%) partial response (PR), 2 of 16 (13%) stable disease (SD), and 12 of 16 (75%) progressive disease (PD). Response rate (RR) was 2 of 16 (13%). Clinical benefit rate (CBR) at 16?weeks was 4 of 16 (25%). Median follow\up was 24.9 months (95% confidence interval [CI], 17.5C30.9). Progression\free survival (PFS) was 2.6 months (95% CI, 1.9C3.1) and overall survival (OS) was 25.5 months (95% CI, 10.4Cnot reached [NR]). Conclusion The combination of enobosarm and pembrolizumab was well tolerated, with a modest clinical benefit rate of 25% at 16?weeks in heavily pretreated AR+ TNBC without preselected programmed death ligand\1 (PD\L1). Future clinical trials combining AR\targeted therapy with immune checkpoint inhibitor (ICI) for AR+ TNBC warrant investigation. =?1 (6%) Response Assessment PR =?1 (6%) Response Assessment SD =?2 (13%) Response Assessment PD =?12 (75%) (Median) Duration Assessments PFS 2.6 months, CI: 1.9C3.1 (Median) Period Assessments OS 25.5 months, CI: 10.4\ (Median) Duration Assessments Duration of Treatment 12 (6C105) weeks Outcome Notes CBR at 16?weeks was 4 of 16 (25%). Durable CR was found in one patient who continues to be progression\free for over 32 months. The median follow\up was 24.9 months (95% CI, 17.5C30.9). PFS was 2.6 months (95% CI, 1.9C3.1) LY 344864 hydrochloride and OS was 25.5 months (95% CI, 10.4CNR). Open in a separate window Adverse Events =?170) [7]. Preclinical evidence has suggested a potential therapeutic synergy by combining AR modulation and PD\1 blockade. Androgens are immunosuppressive and target both innate and adaptive immune systems to dampen the immune response [28, 29, 30, 31, 32, 33, 34]. Inhibition of AR sensitizes malignancy cells to immune\mediated killing. AR suppresses PD\L1 expression by binding to the PD\L1 promotor and directly attenuating PD\L1 gene transcription [29, 30]. In addition, AR signaling inhibits thymocyte production [31], whereas AR blockade has been shown to increase naive T cell generation resulting in a larger diversity of T cell repertoire Rabbit Polyclonal to MP68 that could potentially respond to PD\1 blockade [32, 33]. Moreover, AR blockade yielded increased survival benefits to vaccination in a murine prostate malignancy model [34]. The complementary modes of action and low potential of overlapping toxicities of these two modalities make the combination therapy of AR\targeted agent and immune checkpoint inhibitor a stylish option for AR+ LY 344864 hydrochloride TNBC. A proof\of\concept KEYNOTE\199 trial showed that pembrolizumab plus enzalutamide exhibited a RR of 12% and disease control rate of 51% for patients with metastatic castration\resistant prostate malignancy. We hypothesized that enobosarm could enhance pembrolizumab\induced immune response while targeting AR. The current study was designed to assess the security and efficacy of enobosarm plus pembrolizumab in patients with AR+ mTNBC. A total of 18 patients were enrolled from April 2017 to April 2019. In April 2019, GTx Inc. notified the study team of withdrawal of enobosarm drug supply, and further enrollment was halted. Two patients were ineligible because of undiagnosed brain metastasis. Patient characteristics and treatment variables are explained in Table ?Table11 (=?16). Median age was 64 (range, 36C81), with 50% non\Hispanic white, 31% Hispanic, 13% Asian, and 6% African American. A total of 56% received 0C1 previous lines of therapy, and 44% received 2 prior lines of therapy. Table 1 Patient characteristics =?16)(%)Non\Hispanic White8 (50)Hispanic5 (31)Asian2 (13)African American1 (6)Overall performance status (ECOG), (%)07 (44)19 (56)Histological grade, (%)12 (13)25 (31)39 (56)Initial tumor stage, (%)I6 (38)II8 (50)III2 (13)Median prior lines of therapy for MBC, LY 344864 hydrochloride (%)1 (0\9)03 (18)16 (38)27 (44)Prior surgery, (%)Lumpectomy7 (44)Mastectomy9 (56)Prior radiation, (%)Yes15 (94)No1 (6) Open in a separate window Abbreviations: ECOG, Eastern Cooperative Oncology Group; MBC, metastatic breast cancer. The combination of pembrolizumab and enobosarm was well tolerated. Median dose delay and dose modification were both 0 (range, 0C2). Five of 16 (31%) experienced more than one dose delay, and 3 of 16 (19%) experienced more than one dose reduction. Causes of dose delay and/or dose reduction were grade.