Enzalutamide/Chemotherapy Triplet Shows Promising Activity in Advanced or Recurrent Endometrioid Endometrial Cancer


Patients with advanced or recurrent endometrioid endometrial cancer had promising clinical outcomes following treatment with the combination of enzalutamide and carboplatin plus paclitaxel in the phase 2 ENPAC clinical trial.

Shannon N. Westin, MD

Shannon N. Westin, MD

Patients with advanced or recurrent endometrioid endometrial cancer had promising clinical outcomes following treatment with the combination of enzalutamide (Xtandi) and carboplatin plus paclitaxel in the phase 2 ENPAC clinical trial (NCT02684227), according to results presented during the Society of Gynecologic Oncology (SGO) 2021 Virtual Annual Meeting on Women’s Cancer.1

The study was designed to challenge the standard-of-care chemotherapy combination of carboplatin and paclitaxel which first showed promise as treatment of this patient population in the phase 3 GOG 209 trial (NCT00063999). Carboplatin/paclitaxel demonstrated non-inferiority to the TAP regimen of paclitaxel in combination with doxorubicin and cisplatin in terms of progression-free (PFS) and overall survival (OS). With carboplatin and paclitaxel, the median PFS observed was 14 months and the median OS was 32 months. These results were both comparable to the median PFS and OS observed with the TAP regimen, which was 14 months and 38 months, respectively. The hazard ratios were 1.03 and 1.01, respectively.2

According to Shannon Westin, MD, ENPAC explored another avenue of treatment because recent research suggested that treatment of advanced or recurrent endometrioid endometrial cancer should not follow a “one size fits all” approach.1

“Around that same time, we saw the elegant data from the Cancer Genome Atlas, which demonstrated to us that all endometrial cancers are not created equal. There are clear molecular differences in this disease based on things like copy number aberrations and mutations. And yet, we still treat everyone with that baseline of paclitaxel and carboplatin,” explained Westin, associate professor, Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, The University of Texas MD Anderson Cancer Center, and physician Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery, Lyndon Baines Johnson Hospital in Houston, Texas.

Westin shared that, in fact, androgens are overexpressed in roughly 90% of endometrioid endometrial tumors, which can affect risk for endometrial cancer, tumor histology, tumor grade, growth inhibition in endometrial cancer cell lines, cyclin D1, and the KRAS protein expression. It was hypothesized that an androgen receptor (AR) signaling inhibitor like enzalutamide would help bind androgen to AR even in patients with AR over-expression. This hypothesis was drawn from positive results of enzalutamide as treatment of men with metastatic castrate-resistant prostate cancer after docetaxel therapy who received enzalutamide following treatment with docetaxel. Enzalutamide is approved by the FDA for this indication.

In the safety lead-in ENPAC study, enzalutamide was administered by 40 mg in gelatin capsules at the recommended phase 2 dose of 160 mg daily. Paclitaxel was administered at 175 mg/m2 via intravenous (IV) infusion for once every 3 weeks, and carboplatin was given at AUC 5 IV once every 3 weeks.

The study aimed to determine the clinical activity of enzalutamide combined with carboplatin and paclitaxel based on the coprimay end points of objective tumor response, the number of patients with PFS events for at least 6 months, as well as safety and feasibility. The study was also designed to calculate protein and phosphoprotein expression of AR and AR-response genes after treatment with enzalutamide in match-paired pre-and post-treatment tumor biopsies.

The secondary end points explored in the study included duration of responses (DOR), estimated PFS and OS, and the pharmacokinetic interaction of enzalutamide and paclitaxel. Exploratory end points included molecular results and the synergy enzalutamide may have with other drugs based on the pathways activated following enzalutamide treatment.

Patients enrolled in the ENPAC trial had stage III/IV disease or recurrent disease. All were required to have measurable disease, tumors that were biopsy accessible, an ECOG status of 0 or 1, as well as adequate bone marrow, kidney, and liver function. The study excluded individuals who had non-endometrioid histology of endometrial cancer, had prior chemotherapy aside from cisplatin, had isolated recurrence amenable to curative therapy with radiotherapy or surgery, or predisposing factors for seizure.

The results showed no dose-limited toxicities with enzalutamide plus carboplatin and paclitaxel in the 6 patients assessed.

Following the safety lead-in period, investigators proceeded to phase 2 of the study. In explanation of the phase 2 design, Westin stated “Importantly, in the phase 2 portion of the study, patients did receive 4 weeks of enzalutamide therapy as a single agent. We had pre- and post-treatment biopsies during this lead-in to allow for exploration of the translational objectives I described. Patients were then treated with the 3-drug regimen. Cycles were every 3 weeks, and imaging [occurred] every 3 cycles. Patients could receive up to 9 cycles of therapy.”

Overall, 49 patients were enrolled in the phase 2 portion of the study. At baseline, the population was predominantly White (81.6%) and largely non-Hispanic (85.7%). The median age of patients was 64 years (range, 41-81). The majority of patients also had recurrent disease (86.1%) or stage IV disease (18.4%) at baseline, and grade 2 was the most common baseline grade (53.0%). Most patients were microsatellite stable (59.2%), but 28.6% had microsatellite instability.

Of the patients included in the study, 35 were evaluable for response to enzalutamide plus carboplatin and paclitaxel. After a median of 9 cycles (range, 0-9), the response rate was 71% (95% CI, 54%-85%) and 83% (95% CI, 66%-92%) of patients were progression-free for at least 6 months. For the entire cohort, the median PFS was 11.47 months (95% CI, 9.86-17.94). However, the median PFS was higher for those evaluable for response at 14.42 months (95% CI, 11.2-25.5).

Notably, of those involved in the study, 16.3% were unable to complete treatment with the 30-drug regimen. Three patients discontinued treatment because of rapid disease progression, 2 died because of reasons unrelated to treatment, 2 patients withdrew from the study, and 1 discontinued because of a cerebrovascular event unrelated to study treatment.

In terms of the toxicity profile of enzalutamide with carboplatin and paclitaxel, the most common adverse events (AEs) of any grade were neutropenia (20.4%), anemia (18.4%), and fatigue (18.4%). These AEs were grade 3 or 4 in 18.4%, 14.3%, and 4.1% of patients, respectively. Based on the lack of dose-limiting toxicities and the AEs observed, the combination was considered tolerable in patients with advanced or recurrent endometrioid endometrial cancer.

Analyses for ENPAC are ongoing to assess predictors of response and resistance to androgen-inhibitor therapy.


1. Westin SN, Fellman B, Yuan Y, et al. ENPAC: Phase II study with safety lead-in of enzalutamide in combination with carboplatin and paclitaxel in advanced/recurrent endometrioid endometrial cancer. Presented at: Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021; virtual. Abstract 71.

2. Miller DS, Filaci VL, Mannel RS, et al. Carboplatin and paclitaxel for advanced endometrial cancer: final overall survival and adverse event analysis of a phase III trial (NRG Oncology/GOG0209). J Clin Oncol. 2020;38(33); 3841-3850. doi: 10.1200/JCO.20.01076

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