A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: Dickkopf-related protein 1 (DKK1) is a Wingless-related integrate site (Wnt) signaling modulator that is upregulated in prostate cancers (PCa) with low androgen receptor expression. DKN-01, an IgG4 that neutralizes DKK1, delays PCa growth in pre-clinical DKK1-expressing models. These data provided the rationale for a clinical trial testing DKN-01 in patients with metastatic castration-resistant PCa (mCRPC). METHODS: This was an investigator-initiated parallel-arm phase 1/2 clinical trial testing DKN-01 alone (monotherapy) or in combination with docetaxel 75 mg/m2 (combination) for men with mCRPC who progressed on ≥1 AR signaling inhibitors. DKK1 status was determined by RNA in-situ expression. The primary endpoint of the phase 1 dose escalation cohorts was the determination of the recommended phase 2 dose (RP2D). The primary endpoint of the phase 2 expansion cohorts was objective response rate by iRECIST criteria in patients treated with the combination. RESULTS: 18 pts were enrolled into the study-10 patients in the monotherapy cohorts and 8 patients in the combination cohorts. No DLTs were observed and DKN-01 600 mg was determined as the RP2D. A best overall response of stable disease occurred in two out of seven (29%) evaluable patients in the monotherapy cohort. In the combination cohort, five out of seven (71%) evaluable patients had a partial response (PR). A median rPFS of 5.7 months was observed in the combination cohort. In the combination cohort, the median tumoral DKK1 expression H-score was 0.75 and the rPFS observed was similar between patients with DKK1 H-score ≥1 versus H-score = 0. CONCLUSION: DKN-01 600 mg was well tolerated. DKK1 blockade has modest anti-tumor activity as a monotherapy for mCRPC. Anti-tumor activity was observed in the combination cohorts, but the response duration was limited. DKK1 expression in the majority of mCRPC is low and did not clearly correlate with anti-tumor activity of DKN-01 plus docetaxel.

Enfortumab Vedotin: Nursing Perspectives on the Management of Adverse Events in Patients With Locally Advanced or Metastatic Urothelial Carcinoma.

BACKGROUND: Many patients with locally advanced or metastatic urothelial carcinoma (mUC) need additional treatment options beyond PD-1 or PD-L1 inhibitors and platinum-based chemotherapies. Enfortumab vedotin-ejfv (EV) is an antibody-drug conjugate directed at Nectin-4 that received accelerated approval for treatment of adults with locally advanced or mUC previously treated with PD-1/PD-L1 inhibitors and platinum- containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic settings. OBJECTIVES: This article provides practical considerations and recommendations regarding common and potentially treatment-limiting adverse events that may arise with EV therapy. METHODS: The clinical data that supported the approval of EV are reviewed, and supporting safety and management considerations are provided based on the authors' experience. FINDINGS: EV therapy can be optimized through patient and caregiver education, proactive patient monitoring, early identification of adverse events, and timely intervention to alleviate symptoms.

Outcomes With First-line PD-1/PD-L1 Inhibition in Advanced Urothelial Cancer: A Single Institution Experience.

BACKGROUND: First-line PD-inhibition in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer represents a novel clinical setting, with uncertainty concerning second-line outcomes. Specifying second-line treatment and outcomes will provide guidance in this new sequence. We performed a retrospective chart review to document the outcomes of these patients treated at our institution. PATIENTS AND METHODS: Our cohort consisted of 43 patients with advanced urothelial cancer receiving first-line checkpoint inhibition. Baseline factors, programmed death-ligand 1 (PD-L1) status, treatments, and outcomes during and beyond the first line were obtained. Response was scored using Response Evaluation Criteria in Solid Tumors, version 1.1 criteria. Log rank tests were used to compare outcomes in prognostic subgroups, and outcome associations with PD-L1 status were analyzed with Fisher exact tests. RESULTS: A total of 43 patients received first-line atezolizumab or pembrolizumab from June 2014 until June 2018. The median age was 76.8 years, and the population was 74% male, with 60% having visceral metastases. Reasons for cisplatin ineligibility were Eastern Cooperative Oncology Group performance status 2%, 30%; renal insufficiency, 44%, and both, 21%. First-line objective response rate (ORR) was 30%, and complete response was 14%. The median overall survival was 11.7 months. Of 29 patients progressing, 17 received second-line treatment (most commonly, gemcitabine/carboplatin [10 patients]). The second-line response rate was 33%, and the ORR was 11%. The second-line median overall survival was 6.2 months. No association was found between PD-L1 status and outcomes. CONCLUSION: Outcomes with first-line immunotherapy are consistent with historical outcomes. The ORR after first-line checkpoint inhibition falls short of historical comparators; however, the response rate compares favorably to those of chemotherapies used in previous second-line regimens. The older age and poorer performance status may have contributed to second-line outcomes.