Purpose: Ribociclib, a CDK4/6 inhibitor, demonstrates preclinical antitumor activity in combination with taxanes. We evaluated the safety and efficacy of ribociclib plus docetaxel in a phase Ib/II study in metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: Patients had chemotherapy-naïve mCRPC with progression on ≥ 1 androgen receptor signaling inhibitor (ARSI). The phase II primary endpoint was 6-month radiographic progression-free survival (rPFS) rate, with an alternative hypothesis of 55% versus 35% historical control. Circulating tumor cells (CTC) were collected at baseline and genomically profiled. Result: Forty-three patients were enrolled (N = 30 in phase II). Two dose-limiting toxicities were observed (grade 4 neutropenia and febrile neutropenia). The recommended phase II dose (RP2D) and schedule was docetaxel 60 mg/m2 every 21 days plus ribociclib 400 mg/day on days 1–4 and 8–15 with filgrastim on days 5–7. At the RP2D, neutropenia was the most common grade ≥ 3 adverse event (37%); however, no cases of febrile neutropenia were observed. The primary endpoint was met; the 6-month rPFS rate was 65.8% [95% confidence interval (CI): 50.6%–85.5%; P = 0.005] and median rPFS was 8.1 months (95% CI, 6.0–10.0 months). Thirty-two percent of evaluable patients achieved a PSA50 response. Nonamplified MYC in baseline CTCs was associated with longer rPFS (P = 0.052). Conclusions: The combination of intermittent ribociclib plus every-3-weeks docetaxel demonstrated acceptable toxicity and encouraging efficacy in ARSI-pretreated mCRPC. Genomic profiling of CTCs may enrich for those most likely to derive benefit. Further evaluation in a randomized clinical trial is warranted.

Background: Immune checkpoint inhibitors (ICI) can achieve durable responses in a subset of patients with locally advanced or metastatic urothelial carcinoma (aUC). The use of tumor genomic profiling in clinical practice may help suggest biomarkers to identify patients most likely to benefit from ICI. Methods: We undertook a retrospective analysis of patients treated with an ICI for aUC at a large academic medical center. Patient clinical and histopathological variables were collected. Responses to treatment were assessed for all patients with at least one post-baseline scan or clear evidence of clinical progression following treatment start. Genomic profiling information was also collected for patients when available. Associations between patient clinical/genomic characteristics and objective response were assessed by logistic regression; associations between the characteristics and progression-free survival (PFS) and overall survival (OS) were examined by Cox regression. Multivariable analyses were performed to identify independent prognostic factors. Results: We identified 119 aUC patients treated with an ICI from December 2014 to January 2020. Genomic profiling was available for 78 patients. Overall response rate to ICI was 29%, and median OS (mOS) was 13.4 months. Favorable performance status at the start of therapy was associated with improved OS (HR 0.46, p=0.025) after accounting for other covariates. Similarly, the presence of a TERT promoter mutation was an independent predictor of improved PFS (HR 0.38, p=0.012) and OS (HR 0.32, p=0.037) among patients who had genomic profiling available. Patients with both a favorable performance status and a TERT promoter mutation had a particularly good prognosis with mOS of 21.1 months as compared with 7.5 months in all other patients (p=0.03). Conclusions: The presence of a TERT promoter mutation was an independent predictor of improved OS in a cohort of aUC patients treated with an ICI who had genomic data available. Most of the clinical and laboratory variables previously shown to be prognostic in aUC patients treated with chemotherapy did not have prognostic value among patients treated with an ICI. Genomic profiling may provide important prognostic information and affect clinical decision making in this patient population. Validation of these findings in prospective patient cohorts is needed.

Urothelial carcinoma with squamous differentiation (UCS) is associated with increased resistance to chemotherapy, but outcomes associated with newer therapies approved in this space over the last 5 to 10 years are less well defined. We investigated clinical outcomes and molecular profiling of patients with UCS treated with an immune checkpoint inhibitor (ICI) and/or Enfortumab vedotin (EV). We undertook a retrospective analysis of UC patients treated with ICI and/or EV. Objective response rate (ORR), progression free survival (PFS) and overall survival (OS) were compared between pure UC (pUC) and UCS using X² and log-rank tests, respectively. Prevalence of the most commonly detected somatic alterations were also compared between the 2 histologic subgroups. A total of 160 patients (40 UCS, 120 pUC) were identified for this analysis. Among 151 patients treated with ICI (38 UCS, 113 pUC), UCS patients had a shorter mPFS (1.9 vs. 4.8 months, P < 0.01) and mOS (9.2 vs. 20.7 months, P < 0.01) compared to pUC. Among 37 patients treated with EV (12 UCS, 25 pUC), UCS patients had a lower ORR (17% vs. 70%, P < 0.01) and shorter mPFS (3.4 vs. 15.8 months, P < 0.01). UCS samples were enriched for CDKN2A, CDKN2B, PIK3CA, while pUC samples were enriched for ERBB2 alterations. In this single-center retrospective analysis, patients with UCS had a distinct somatic genomic profile relative to patients with pUC. Patients with UCS also had inferior outcomes to ICIs and EV compared to patients with pUC.