An Open-Label, Single-Arm, Phase 2 Trial of the Polo-Like Kinase Inhibitor Volasertib (BI 6727) in Patients With Locally Advanced or Metastatic Urothelial Cancer

Abstract

BACKGROUND

Polo-like kinases (Plks) control multiple steps during the cell cycle, and Plk1 is overexpressed in urothelial cancer (UC). Volasertib (BI 6727), a Plk inhibitor, has demonstrated antitumor activity in several malignancies, including UC. In this phase 2 trial, the authors investigated volasertib as a second-line treatment in advanced/metastatic UC.

METHODS

Patients who progressed within 2 years of 1 prior chemotherapy regimen received 300 mg volasertib on day 1 every 3 weeks. The dose was escalated to 350 mg in cycle 2 if volasertib was tolerated in cycle 1. The primary endpoint was tumor response, which was assessed every 6 weeks; secondary endpoints were progression-free survival, overall survival, duration of response, safety, and pharmacokinetics.

RESULTS

Fifty patients were enrolled, and the median patient age was 68.5 years (range, 52-83 years). All patients had received prior platinum, 94% of patients had relapsed ≤2 years after prior therapy, 36% had liver metastases, and 54% had lung metastases. The median number of treatment cycles was 2 (range, 1-27 treatment cycles), and 23 patients were dose escalated at cycle 2. Seven patients (14%) had a partial response, 13 (26%) had stable disease, and 30 (60%) progressed within 6 weeks. The median response duration was 41 weeks (range, 29.1-77.3 weeks). The median progression-free survival was 1.4 months, and the median overall survival was 8.5 months. The most frequent grade 3 and 4 adverse events were neutropenia (28%), thrombocytopenia (20%), and anemia (16%). No cumulative toxicity was observed.

CONCLUSIONS

Volasertib as second-line treatment for advanced/metastatic UC had an acceptable safety profile but demonstrated insufficient antitumor activity for further evaluation as a monotherapy.

INTRODUCTION

Urothelial carcinoma (UC) has an annual worldwide incidence of 382,660 cases with an estimated 150,282 deaths each year.¹ In industrialized countries, UC is the fourth most common cancer (excluding sex-specific malignancies)¹; and, in the United States, there are an estimated 72,570 new cases and 15,210 deaths per year.² On the basis of data from randomized clinical trials, the standard first-line treatment for metastatic UC is cisplatin-based combination chemotherapy.^3-7 In 1 large, prospective phase 3 trial of 2 cisplatin-based combination therapies, gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), demonstrated similar overall response rates (GC, 49%; MVAC, 46%), including similar complete response (CR) rates (approximately 12% in both arms)⁵ and a similar median overall survival (mOS) (GC, 13.8 months; MVAC, 14.8 months).⁶ However, long-term follow-up indicated that only a small proportion achieved long-term progression-free survival (PFS) (GC, 9.8%; MVAC, 11.3% at 5 years).⁶

For patients who relapse after first-line chemotherapy, the prognosis is generally poor⁸; there are no Food and Drug Administration-approved agents in the United States for this disease setting. In Europe, vinflunine (Javlor; Pierre Fabre Limited, Castres, France), a microtubule inhibitor, is approved as a second-line therapy for advanced UC based on a phase 3 trial of vinflunine plus best supportive care (BSC) versus BSC alone in cisplatin-refractory patients.⁹ Vinflunine led to an improved median PFS (mPFS) (3.0 months vs 1.5 months; P = .001) and an improved mOS by approximately 2 months compared with BSC alone (6.9 months vs 4.3 months; P = .040) but did not demonstrate a significant overall survival (OS) advantage in the intent-to-treat analysis. Consequently, there is a need to identify novel targets and to develop more efficacious treatments for patients with UC who fail or who cannot tolerate first-line cisplatin-based therapy.

Polo-like kinases (Plks), a family of 5 key serine/threonine kinases (Plk1-Plk5) involved in cell division and mitosis, represent a promising target. Plk1 is involved in the passage of cells through the G2/M checkpoint and mitosis, and Plk1 overexpression has been reported in a range of human cancers, including nonsmall cell lung cancer, prostate cancer, ovarian cancer, breast cancer, colorectal cancer, and UC.^10-14 Furthermore, patients with UC whose tumors overexpressed Plk1 had a higher pathologic tumor grade (P = .0024) and multiple tumors (P = .0241) compared with those who did not have Plk1 overexpression, suggesting that Plk1 promotes tumorigenesis.¹³

Volasertib (an investigational agent; Boehringer Ingelheim, Ingelheim, Germany) is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plk.¹⁵ In preclinical studies, volasertib inhibited the proliferation of multiple UC cell lines (data on file; Boehringer Ingelheim) and demonstrated the ability to promote mitotic arrest and apoptosis in UC cells.¹⁶ Two phase 1 trials of volasertib in solid tumors reported partial responses (PRs) in patients who had heavily pretreated, metastatic UC.^17,18 Here, we report the results of a phase 2 trial investigating the efficacy, safety, and pharmacokinetic (PK) profile of volasertib in the second-line treatment of patients with advanced or meta-static UC.

MATERIALS AND METHODS

Trial Design

This was a single-arm, open-label, multicenter phase 2 study of volasertib as second-line treatment for patients with locally advanced, metastatic UC after failure of first-line systemic therapy (registered as National Clinical Trial NCT01023958). The primary endpoint was the objective tumor response rate, defined as CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included PFS, OS, duration of response, safety, and PK.

Patient Selection

Patients aged ≥18 years were eligible for this study if they had histologically or cytologically confirmed, metastatic or unresectable UC of the bladder, ureters, or renal pelvis after first-line systemic chemotherapy, or after initial surgery plus adjuvant/neoadjuvant chemotherapy, or after chemoradiation. Recurrence was defined as relapse within 2 years after cessation of prior chemotherapy and was confirmed by imaging. Inclusion criteria were measurable disease by standard cross-sectional imaging according to RECIST 1.1, an Eastern Cooperative Oncology Group (ECOG) performance score (PS) ≤2, and a life expectancy of at least 3 months. Exclusion criteria were the receipt of >1 prior regimen of chemotherapy (including prior adjuvant or neoadjuvant therapy) and the presence of brain metastases. Patients also were excluded if they had inadequate organ function (defined as absolute neutrophil count <1500/μL, platelet count <100,000/μL, hemoglobin <9 g/dL, creatinine >1.5 times the upper limit of normal [ULN], total bilirubin >1.5 mg/dL, or aspartate amino transferase and/or alanine amino transferase level >2.5 times the ULN [>5 times the ULN in case of known liver metastases]); serious concomitant illnesses (including QTcF prolongation [eg QTcF >470 msec] or congenital long QT syndrome); other active malignancy diagnosed within the past 3 years (except nonmelanoma skin cancer and cervical intraepithelial neoplasia); or who had received chemotherapy, radiotherapy, or immunotherapy within the past 4 weeks. The study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and with Good Clinical Practice as defined by the International Conference on Harmonization. All participating patients gave written informed consent.

Treatment

Volasertib was administered by 2-hour intravenous infusion at a dose of 300 mg once daily on day 1 of 21-day treatment cycles. This dose was defined as the recommended dose for phase 2 trials from a dose-escalation clinical phase 1 trial.¹⁷ The maximum tolerated dose of volasertib in this trial was determined to be 400 mg; however, serious but variable drug-related adverse events (AEs) were reported at doses of 350 mg or higher. Dose escalation to 350 mg was allowed at the treating physician’s discretion for cycle 2 and beyond if the disease was stable and treatment-related AEs were manageable (defined as the absence of unacceptable AEs: drug-related nonhematologic AEs grade ≥3 [except emesis or diarrhea responding to supportive treatment], drug-related grade 4 neutropenia for ≥7 days or complicated by infection, or drug-related grade 4 thrombocytopenia). In the case of unacceptable AEs, volasertib was omitted until recovery and was then reduced by 50 mg for the ensuing treatment cycles. Serial dose reductions were permitted; however, no dose reductions below 200 mg were allowed. Continuation of treatment with repetitive cycles was allowed in patients who had clinical benefit until they developed disease progression or unacceptable AEs.

Investigations

At baseline, medical history, physical examination, assessment of ECOG PS, electrocardiogram (ECG), and laboratory assessment of hematology, biochemistry, and coagulation parameters were performed. Baseline disease assessments by computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, chest, abdomen, and pelvis were performed within 4 weeks before starting treatment. Routine CT/MRI scans of the chest, abdomen, and pelvis were performed at the end of each even-numbered cycle thereafter until progression. If patients discontinued treatment without documented radiologic progression, then CT/MRI scans were performed at the end-of-treatment visit and every 6 weeks thereafter until progression, start of another anticancer treatment, or loss to follow-up. After initial screening, a CT/MRI scan of the brain was performed only upon clinical suspicion of brain metastasis. After radiologic progression, patients were followed every 3 months until loss to follow-up or death.

Tumor response, the primary endpoint, was assessed according to RECIST 1.1. Secondary endpoints were PFS (time from first treatment to progression or death), OS (time from first treatment to death), duration of overall response (time from first response [CR or PR] to progression or death), duration of disease control (time from best overall response of CR, PR, or stable disease [SD; defined as neither sufficient shrinkage to qualify for a PR nor sufficient increase to qualify for disease progression ≥6 weeks of therapy] to progression or death). All AEs, including unacceptable toxicities that occurred during the course of the study, were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. All patients who received at least 1 dose of volasertib were included in the safety analyses.

Pharmacokinetic Analysis

PK analysis was performed to determine the plasma concentrations of volasertib during treatment cycles 1 and 2. In cycle 1, blood samples were taken before volasertib administration (0 hours), immediately before the end of drug infusion (2 hours), and then at 3 hours and 6 hours postadministration; further samples were taken on days 2, 8, and 15. In cycle 2, samples were taken on day 1 before administration and at 2 hours postadministration. The concentration of volasertib was determined using a fully validated high-performance liquid chromatography-tandem mass spectrometry technique as described previously.¹⁵

Statistical Analysis

This study had a 2-stage design (modified Gehan) with progression to the second stage dependent on an interim analysis. The sample size for this trial was based on having a lower 95% confidence interval (CI) of at least 10% if a RECIST-defined response rate of ≥20% was observed. An informal interim analysis was planned once 20 evaluable patients had received 4 courses of volasertib (or had discontinued because of unacceptable AEs or progressive disease). If ≥2 of 20 patients achieved a CR and/or a PR at any time within the first 4 treatment cycles of volasertib, then the trial could proceed to the second stage. In the second stage, recruitment would be expanded to a total of 50 patients.

RESULTS

Patient Disposition and Demographics

In total, 62 patients from 20 centers in 2 countries (the United States and Taiwan) were screened, and 50 patients were treated. As of the January 17, 2012 clinical cutoff date, all patients had discontinued treatment. Reasons for treatment discontinuation were progressive disease (n = 48), AE (n = 1 [grade 4 neutropenia and thrombocytopenia]), and refusal to continue study medication (n = 1).

The median patient age was 68.5 years (range, 52-83 years), and 80% of patients were men (Table 1). The majority of patients (94%) had a baseline ECOG score ≤1, and most patients (82%) had a baseline hemoglobin value ≥10 g/dL. Seventy-two percent of patients had received prior treatment with cisplatin-based therapy, and the remaining 28% had received carboplatin-based therapy. The majority of patients (94%) had relapsed within 2 years after prior therapy.

TABLE 1.

Patient Demographics

Variable	No. of Patients (%), N = 50
Age: Median [range], y	68.5 [52-83]
Age ≥65 y	37 (74)
Percentage of men/women	80/20
Baseline ECOG PS
0	26 (52)
1	21 (42)
2	3 (6)
Primary site region
Urinary bladder	30 (60)
Renal pelvis/ureter/urethra	20 (40)
No. of metastatic sites
1-2	32 (64)
>2	18 (36)
Metastatic site
Lung	27 (54)
Lymph node	26 (52)
Lymph node only	7 (14)
Liver	18 (36)
Bone	7 (14)
Adrenal glands	3 (6)
Other	15 (30)
Time from last chemotherapy to  baseline imaging
≤6 mo	22 (44)
>6 mo	27 (54)
Missing	1 (2)
Type of prior platinum-base  chemotherapy
Cisplatin	36 (72)
Carboplatin without cisplatin	14 (28)
Baseline hemoglobin value <10 g/dL	6 (12)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; PS, performance score.

Treatment Exposure

Patients received a median of 2 cycles of volasertib (range, 1-27 cycles). The volasertib dose was escalated to 350 mg in cycle 2 in 23 patients, and only 3 patients required subsequent dose reductions (1 patient each in cycles 3, 6, and 9).

Efficacy

At the preplanned interim efficacy analysis, 2 of the first 20 patients who completed 4 treatment cycles achieved a PR. Consequently, the study proceeded to the second stage with a total of 50 patients treated. At the final analysis, the overall response rate was 14% (95% CI, 0.73%-0.94%), and 7 patients achieved a PR as their best overall response with a median response duration of 41.0 weeks. An additional 13 patients (26%) had SD, resulting in a disease control rate of 40% (Table 2, Fig. 1). The median duration of disease control was 27.0 weeks, the mPFS was 6.1 weeks (95% CI, 5.6-11.1 weeks), and the mOS was 8.5 months (95% CI, 3.9-12.1 months).

TABLE 2.

Best Overall Response and Time-Related Parameters

Variable	Total, N = 50
Response: No. of patients (%)
PR	7 (14)
SD	13 (26)
Disease control: PR + SD	20 (40)
Duration of PR: Median/range, wk	41.0/29.1-77.3
Duration of disease control,  PR or SD: Median/range, wk	27.0/10.1-77.3
PFS: Median [95% CI], wk	6.1 [5.6-11.1]
PFS rate, %
At 3 mo	32
At 6 mo	20
OS: Median [95% CI], mo	8.5 [3.9-12.1]
OS rate, %
At 3 mo	77.2
At 6 mo	55.5

Abbreviations: CI, confidence interval; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease.

Figure 1.

This is a summary of the best overall responses. Patients are sorted according to the maximum decrease in target lesion size. PD indicates progressive disease; PR, partial response; SD, stable disease; RECIST, Response Evaluation Criteria in Solid Tumors.

A subgroup analysis was performed to assess the effect of dose escalation to volasertib 350 mg on response and survival. In general, patients who did not escalate presented with more advanced disease (metastatic liver lesions [44% vs 26%], ECOG PS ≥1 [59% vs 35%], >2 target lesions [44% vs 26%], and time from prior chemotherapy to study entry ≤6 months [52% vs 35%]) than those who escalated to volasertib 350 mg. In patients who escalated to volasertib 350 mg, 21.7% achieved a PR, and the mPFS and mOS were 11.1 weeks and 10.6 months, respectively. PRs were achieved in 7.4% of patients who did not escalate, and their mPFS and mOS were 6.0 weeks and 5.8 months, respectively. A post hoc subgroup analysis was performed to assess the impact of time to disease progression after the most recent chemotherapy (≤6 months vs >6 months) before study entry on the efficacy of volasertib. Similar response rates (14% vs 15%, respectively) were observed in both subgroups; however, patients whose disease progressed >6 months after their last chemotherapy before study entry had a prolonged mPFS (5.6 weeks vs 10.1 weeks).

Safety

Dose reductions because of unacceptable toxicities occurred in 4 patients in cycle 1 and in a total of 7 patients (14%) overall (Table 3). Cycle 1 AEs that resulted in a dose reduction from 300 mg to 250 mg in 4 patients were neutropenia (n = 1), ECG QT prolongation (n = 1), thrombocytopenia (n = 1), and neutropenia and thrombocytopenia (n = 1). Overall, 98% of patients reported at least 1 AE during the study (Table 4). The most common AEs (all grades) irrespective of their relation to the study drug were fatigue, anemia, thrombocytopenia, nausea, decreased appetite, constipation, and neutropenia. Grade 3 and 4 AEs that occurred in ≥10% of the total study population were neutropenia, thrombocytopenia, and anemia (Table 4). Only 1 episode of febrile neutropenia (grade 3) was reported and was resolved within 13 days without complications. One patient experienced a grade 3 QTc prolongation during the first course of volasertib that recovered to predose values within 6 hours. The predose ECG revealed a grade 1 QTcF prolongation and a right bundle branch block. The patient had a history of hypertension. No clinically relevant side effect, such as arrhythmias or cardiac dysfunction, was reported in relation to volasertib administration. Three patients died during the study because of disease progression; none of those deaths were attributed to the study treatment.

TABLE 3.

Patients With Adverse Events Leading to Dose Reductions

Adverse Event	No. of Patients (%)	Dose Reduction [No.]
Thrombocytopenia	3 (6)	350→300 mg [1]
		300→250 mg [2]a
Neutropenia	2 (4)	300→250 mg [2]a
Diarrhea	1 (2)	350→300 mg [1]
Nausea	1 (2)	350→300 mg [1]
Fatigue	1 (2)	350→300 mg [1]
ECG: Prolonged QT	1 (2)	300→250 mg [1]a

Abbreviations: ECG, electrocardiogram.

^aThese adverse events occurred in cycle 1.

TABLE 4.

Adverse Events (All Treatment Cycles), Whether Drug-Related or Not, That Occurred in ≥10% of the Total Study Population

	No. of Patients (%), N = 50
Adverse Event	All Grades	Grade ≥3
Total	49 (98)	31 (62)
Fatigue	29 (58)	2 (4)
Anemia	22 (44)	8 (16)
Thrombocytopenia	19 (38)	10 (20)
Nausea	19 (38)	0 (0)
Decreased appetite	18 (36)	2 (4)
Constipation	17 (34)	1 (2)
Neutropenia	16 (32)	14 (28)
Back pain	11 (22)	2 (4)
Diarrhea	11 (22)	1 (2)
Cough	10 (20)	0 (0)
Dizziness	7 (14)	0 (0)
Dyspnea	7 (14)	0 (0)
Dehydration	7 (14)	2 (4)
Urinary tract infection	7 (14)	3 (6)
Anxiety	6 (12)	0 (0)
Insomnia	6 (12)	0 (0)
Vomiting	6 (12)	0 (0)
Asthenia	5 (10)	1 (2)
Pyrexia	5 (10)	1 (2)
Leukopenia	5 (10)	1 (2)

Pharmacokinetics

Volasertib demonstrated multiexponential PK behavior. Plasma concentrations generally increased until the end of infusion and then declined rapidly, followed by several slower elimination phases. The maximal plasma concentration (C_max) of volasertib was 253 ng/mL at a time (t_max) of approximately 2 hours (range, 1.53-4.17 hours). The geometric mean volume of distribution (V_ss) was 7470 liters, suggesting extensive tissue distribution (Table 5). The apparent terminal half-life (t_1/2) averaged 150 hours, with a mean residence time (MRT) of 136 hours. The total plasma clearance was moderate, with a geometric mean value of 914 mL/minute after infusion of volasertib 300 mg. The PK profile of volasertib was not significantly affected by sex, age, weight, body mass index, or body surface area (data not shown).

TABLE 5.

Noncompartmental Pharmacokinetic Parameters After the First 2 Hours of Intravenous Infusion of 300 mg Volasertib

Parameter	No. of Patients	Geometric Mean	Geometric Coefficient of Variation, %
AUC0-∞, ng·h/mL	48	5470	30.6
Cmax, ng/mL	47	253	51.9
t1/2, h	48	150	17
tmax, h	47	Median, 2.03	Range, 1.53-4.17
CL, mL/min	48	914	30.6
MRT, h	48	136	21.5
Vss, liter	48	7470	32.4

Abbreviations: AUC, area under the plasma concentration time curve; CL, apparent clearance of the analyte in plasma after administration; C_max, maximum measured concentration of the analyte in plasma; MRT, mean residence time; t_1/2, terminal half-life; t_max, time from dosing to the maximum concentration of the analyte in plasma; V_ss, volume of distribution at steady state.

DISCUSSION

In this phase 2, open-label trial, we descriptively evaluated the activity of single-agent volasertib as a second-line treatment for advanced/metastatic UC. Volasertib demonstrated an acceptable safety profile. Antitumor activity was modest with a response rate of 14% (all PRs), which did not meet prespecified criteria for sufficient activity to justify further study as a single agent in this disease. This modest activity is comparable to that observed in phase 2 trials of other single agents in this setting that reported response rates ranging from 3% to 44%.⁸ Similarly, the mPFS observed with volasertib in the current trial was only 6.1 weeks (1.4 months); however, 16 patients (32%) had a PFS >90 days (3 months), and 10 patients (20%) had a PFS >180 days (6 months), suggesting that there may be a subgroup of patients who benefited. PK analyses confirmed that the modest activity of volasertib observed in this study was not a result of poor tissue distribution or circulating plasma levels. Volasertib demonstrated multiexponential PK behavior with extensive tissue distribution and moderate clearance, comparable to that observed in other studies of volasertib as monotherapy or in combination with other agents.^17-19

Approximately half of the patients (46%) in this study were able to escalate to 350 mg, indicating the generally manageable safety profile of volasertib. A higher response rate (22% vs 7%) and prolonged mPFS (11.1 weeks vs 6 weeks) and mOS (10.6 months vs 5.8 months) were observed in patients who escalated to 350 mg volasertib. The seemingly better outcome in the higher volasertib dose group is likely attributable to an imbalance of risk factors at baseline across the 2 dosing groups, with the higher volasertib dose group having more favorable baseline characteristics compared with those who were not able to escalate. This hypothesis is consistent with the findings of a univariate analysis performed to determine the association of various potential prognostic factors with PFS (data not shown), which demonstrated that a hemoglobin level <10 g/dL, the presence of liver lesions, and the presence of more than 1 risk factor (defined as an ECOG PS >0, hemoglobin <10 g/dL, or the presence of liver lesions) were associated with a shorter PFS.

Compared with other reports from second-line, single-agent studies,⁸ more patients in the current study presented with 2 or 3 poor prognostic factors at baseline. Moreover, a relatively large proportion of patients (40%) had nonbladder primaries, which were associated with poorer outcomes in a first-line phase 3 trial.²⁰ The observed mOS for patients who presented with 0 (n = 17), 1 (n = 18), and 2 (n = 13) prognostic factors in this trial was similar to historic data on mOS (14.3 months, 8.5 months, and 2.9 months compared with 14.2 months, 7.3 months, and 3.8 months, respectively).²¹ Only 2 patients in the current study presented with 3 prognostic factors, so a similar comparison of mOS in this subgroup would not be meaningful. Recently, the 3 aforementioned prognostic risk factors (ECOG PS >0, hemoglobin <10 g/dL, and the presence of liver lesions) were refined further to include an additional factor: time from prior chemotherapy.²² These factors may need to be considered as stratification factors in future trial designs. Notably, other recently reported, nonrandomized phase 2 trials evaluating pazopanib and nanoparticle albumin-bound paclitaxel demonstrated modest activity but also were plagued by difficulties interpreting the overall results.^23,24

Currently, there is no established standard of care for patients who experience relapse after first-line therapy, or are refractory to first-line therapy, or are unsuitable for cisplatin-based therapy.²⁵ The limited antitumor activity of single-agent volasertib and the relatively short PFS observed in this trial do not support its continued development as second-line monotherapy in a population of patients with UC as a single agent. However, the safety profile was acceptable, with primarily modest and reversible myelosuppression (and only minor nonhematologic AEs). In addition, preclinical studies have demonstrated that the combination of a Plk inhibitor and cisplatin resulted in improved efficacy in both in vitro and murine xenograft models compared with cisplatin alone.¹⁶ Preliminary evidence from a phase 1 trial in patients with solid tumors demonstrated encouraging antitumor activity and an acceptable safety profile of volasertib in combination with cisplatin or carboplatin.¹⁹ Thus, further investigation of volasertib in combination with chemotherapy or biologic agents in advanced UC may be considered.

In summary, although this phase 2 trial demonstrated an acceptable safety profile for volasertib as a second-line treatment for patients with advanced or metastatic UC, the study demonstrated only modest antitumor activity. Compared with historic controls, clinical outcomes in this study in terms of response rate and PFS were at the low end of the expected range. A contributing factor may have been the higher proportion of patients with a comparably worse prognosis who were treated on this study. Additional bio-marker studies would be beneficial to better understand the role of Plk inhibition in tumor development and anti-cancer therapy. Before the initiation of further clinical trials in UC investigating volasertib treatment as single agent or in combination with other compounds, a better understanding of the mode of action of Plk inhibition and possible patient selection parameters may be warranted.