Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure
Article first published online: 29 AUG 2012
© 2012 The Authors BJU International © 2012 BJU International
Volume 111, Issue 1, pages 44–52, January 2013
How to Cite
Meulenbeld, H. J., Bleuse, J. P., Vinci, E. M., Raymond, E., Vitali, G., Santoro, A., Dogliotti, L., Berardi, R., Cappuzzo, F., Tagawa, S. T., Sternberg, C. N., Jannuzzo, M. G., Mariani, M., Petroccione, A. and de Wit, R. (2013), Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure. BJU International, 111: 44–52. doi: 10.1111/j.1464-410X.2012.11404.x
- Issue published online: 20 DEC 2012
- Article first published online: 29 AUG 2012
- aurora kinase;
- aurora kinase inhibitor;
- castration-resistant prostate cancer;
What's known on the subject? and What does the study add?
- Since their discovery aurora kinases have been identified as a potential target in anticancer therapy and currently many aurora-selective small molecule kinase inhibitors are in development. Aurora kinases play an essential role as key mitotic regulators and are frequently overexpressed in prostate cancer. In vivo data in the transgenic mouse prostate carcinoma model revealed tumour regressions of >80% in three out of 16 animals and disease stabilizations in 10 out of 16 animals treated with danusertib. Two phase I dose escalation studies with danusertib in patients with advanced solid tumours were performed, which established two doses and schedules for phase II studies. However, the preliminary data of the available phase II studies with danusertib in solid tumours showed limited activity. Danusertib may yield more activity in the treatment of leukaemias than in solid tumours. Danusertib is generally well tolerated with neutropenia as the main dose limiting toxicity.
- This phase II study determined the efficacy and toxicity of danusertib administered intravenously over two different dosing schedules in patients with metastatic castration-resistant prostate cancer (CRPC) with progressive disease after docetaxel-based treatment. Danusertib showed in vivo antitumour activity in prostate cancer models and clinically relevant disease stabilizations were observed in several patients with solid tumours in phase I studies. However, our study revealed that monotherapy with danusertib, although well tolerated, showed only limited activity in the treatment of patients with CRPC. In view of the new advances in the treatment of patients with CRPC and the negative result of our study it is unlikely that danusertib will be further explored for the treatment of patients with CRPC. Further studies are required to establish specific biomarkers predictive for either response or prolonged disease stabilization to select subsets of patients with CRPC who may benefit from treatment with danusertib.
- To determine the efficacy and toxicity of danusertib (formerly PHA-739358) administered i.v. over two different dosing schedules with equivalent dose intensity in patients with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment.
Patients and Methods
- In this open-label, multicentre phase II trial 88 patients were randomly assigned (1:1 ratio) to receive either danusertib 330 mg/m2 over 6 h i.v. on days 1, 8 and 15 (arm A, n = 43) or 500 mg/m2 over 24 h i.v. on days 1 and 15 (arm B, n = 38), every 4 weeks.
- The primary endpoint chosen for this exploratory study was PSA response rate at 3 months.
- Sixty patients (31/43 in arm A and 29/38 in arm B) were evaluable for the primary endpoint.
- Median progression-free survival was 12 weeks in both arms.
- PSA response occurred in one patient in each arm; best overall response was stable disease in eight (18.6%) and 13 (34.2%) patients in arms A and B, respectively.
- Eleven out of 81 (13.6%) treated patients had stable disease for ≥6 months.
- Danusertib was generally well tolerated; the most common grade 3 and 4 drug-related adverse event was neutropenia which occurred in 37.2% (arm A) and 15.8% (arm B) of the patients.
- Danusertib monotherapy shows minimal efficacy in patients with castration-resistant prostate cancer. Further studies are required to establish specific biomarkers predictive for either response or prolonged disease stabilization.
castration-resistant prostate cancer
Response Evaluation Criteria in Solid Tumors
- ECOG PS
Eastern Cooperative Oncology Group performance status
National Cancer Institute Common Terminology Criteria for Adverse Events
neuroendocrine prostate cancer
For more than 70 years androgen deprivation therapy has been the standard of care for patients with advanced prostate cancer, but eventually patients uniformly progress to a state of castration-resistant prostate cancer (CRPC) . At the initiation of this study the only approved therapy that had been shown to prolong survival in patients with CRPC was docetaxel-based chemotherapy . Treatment options for patients whose disease progresses after docetaxel treatment was an unmet medical need. Recently, this clinical landscape has been altered by the results of phase III trials with cabazitaxel , abiraterone acetate , enzalutamide  and radium-223 chloride . Although treatment options have increased, patients still have a poor prognosis and novel rational approaches are needed.
Aurora kinases play an essential role as key mitotic regulators, controlling entry into mitosis, centrosome function, chromosome assembly and segregation . Since aurora kinases are typically overexpressed in prostate cancers  and probably facilitate progression of prostate cancer, targeted inhibition of these kinases may offer therapeutic benefit. Danusertib (formerly PHA-739358) is a potent small-molecule 3-aminopyrazole derivative that inhibits all aurora kinases . In vivo data in the transgenic mouse prostate carcinoma model revealed tumour regressions of >80% in three out of 16 animals and disease stabilizations in 10 out of 16 animals treated with danusertib [10, 11]. Two parallel phase I dose escalation studies with danusertib in patients with advanced solid tumours were performed [12, 13]. Two phase II doses and schedules were established. A weekly regimen applies 330 mg/m2 administered over 6 h i.v. and a 2-weekly regimen applies 500 mg/m2 administered over 24 h i.v. The main dose limiting toxicity observed was grade 3–4 neutropenia. Based on these considerations and preclinical data supporting substantial efficacy of danusertib in prostate cancer the current study was designed to assess the antitumour activity of danusertib in patients with docetaxel-refractory metastatic CRPC.
Patients and Methods
Eligible patients had metastatic CRPC with disease progression after treatment with docetaxel chemotherapy. For patients with measurable disease, progressive disease was defined according to the Response Evaluation Criteria in Solid Tumors (RECIST) . For patients without measurable disease, progressive disease was defined as the appearance of new metastases on bone scan in combination with PSA progression, according to the criteria of the PSA Working Group .
Additional eligibility criteria included Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2; age ≥18 years; life expectancy ≥3 months; castrate levels of testosterone; and haematological and chemical laboratory values that met predefined criteria. Patients receiving bisphosphonates must have been on stable doses for at least 4 weeks. Exclusion criteria were more than one previous chemotherapy regimen, treatment within the previous 28 days with radiotherapy or investigational drugs, CNS involvement, uncontrolled infection, clinically significant vascular disease, uncontrolled hypertension and other prior malignancy except for non-melanoma skin cancer or superficial bladder cancer.
Corticosteroids had not to be initiated during the study period unless mandated by patient clinical condition. Initiation or increase in dose of corticosteroids during the study period, as they might reduce PSA levels, rendered the patient not evaluable for the primary endpoint.
Patients provided written informed consent before enrolment. The study was conducted according to the Declaration of Helsinki and in compliance with good clinical practice and local ethical and legal requirements.
This open-label, non-comparative, multicentre, randomized phase II study was designed in two sequential parts. The first part, presented here, was performed to select the best dose schedule of danusertib based on PSA responses. If there were three or more out of 29 evaluable patients per arm with a PSA response, the second part would be initiated. The second part would consist of a randomized, open-label comparison of the selected dose schedule of danusertib with mitoxantrone or an approved second-line treatment if any agent, at the time of initiating the second part of the study, was approved for this indication. Patients were centrally randomly assigned in a 1:1 ratio to treatment with either danusertib 330 mg/m2 over 6 h i.v. on days 1, 8 and 15 (arm A) or danusertib 500 mg/m2 over 24 h through a central venous catheter on days 1 and 15 (arm B), every 4 weeks.
Patients were stratified by PSA response to prior docexatel chemotherapy (≥50% PSA decline vs <50% PSA decline). Danusertib was continued until disease progression, unacceptable toxicity or patient refusal.
The primary endpoint was PSA response rate within the first 3 months of treatment. PSA response was defined as ≥50% decline in serum PSA concentration compared with baseline, confirmed at least 4 weeks later. Secondary endpoints included duration of PSA response, 30% PSA reduction rate, and objective tumour response rate according to RECIST criteria. All responses had to be confirmed. Analyses of PSA endpoints were only performed in patients with documented PSA progression at study entry.
Other secondary endpoints were progression-free survival (PFS), clinical benefit rate and safety. For patients without measurable disease, progressive disease was defined as the appearance of more than one new lesion outside the bone or two or more new bone lesions or one new bone lesion associated with PSA progression. For patients with measurable disease, progression was defined according to RECIST criteria.
To take the new recommendation of the Prostate Cancer Clinical Trials Working Group 2  into consideration the protocol was amended to change the definition of PSA progression. PSA progression was defined as increase of ≥25% over nadir PSA concentration provided that the increase in the absolute PSA value was ≥2 ng/mL. PSA increase only did not qualify for progression within the first 12 weeks of treatment.
The clinical benefit was assessed based on evaluation of tumour pain, analgesic consumption and performance status. Pain was assessed with a standard 10-point pain numerical scale and analgesic consumption with a five-point analgesic scale . Clinical benefit was defined as a ≥2-point decrease in pain score with stable or reduced analgesic score or a ≥1-point decrease of analgesic score with stable or reduced pain score compared with baseline lasting ≥2 weeks and without deterioration in performance status. Toxicity was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (Version 3.0).
Tumour assessments consisting of a bone scan, chest X-ray or CT scan, and abdominal CT scan or MRI, were performed at baseline, every three cycles and at the end of treatment. PSA was measured before each cycle. All assessments were repeated to confirm a response 4 weeks after the response was observed. Pain and analgesic consumption were assessed at baseline, on days 1 and 15 of every cycle, at the end of treatment and then every month until progression or further antitumour therapy. Safety evaluations were performed throughout the study.
Simon's two-stage minimax design was used to determine the sample size and interim decision criteria . Assuming that a PSA response rate of 20% in evaluable patients would indicate potential usefulness, whereas a rate of 10% would be the lower limit of interest, with α = 0.10 and β = 0.20 the estimated accrual number for the first part was 29 evaluable patients for each randomized schedule. In the case of three or more PSA responses out of 29 evaluable patients in one of the arms in the first part, the second part would be initiated. In the second part of the study 54 additional patients would be randomized between treatment with the selected dose schedule of danusertib (27 patients) or mitoxantrone or an approved second-line treatment (27 patients). If nine or more out of the total of 56 patients treated with the selected dose schedule of danusertib had a PSA response after this second step, it was to be concluded that the efficacy of the regimen warranted further investigation.
PFS and duration of PSA response were estimated by the Kaplan–Meier method. No comparative analyses were performed to detect a statistical difference between treatment arms.
Patients and Treatment
From September 2007 through October 2009, 88 patients were randomized and 81 were treated. The main reasons for not receiving study treatment were deterioration of the laboratory values or health condition and withdrawal of consent (Fig. 1).
Of the 81 treated patients, 60 patients (31/43 arm A and 29/38 arm B) were evaluable for the primary endpoint. The major reasons for non-evaluability were one or no PSA assessment on treatment, increase in dose of corticosteroids on treatment and radiological progression but no PSA progression before study entry (Fig. 1). The two dose groups were well balanced for baseline characteristics, except for the number of patients with liver metastases and corticosteroid and bisphosphonate use (Table 1).
|Patient characteristics||Arm A (N = 43)||Arm B (N = 38)|
|Median (range)||68.3 (48–80)||67.9 (50–80)|
|≥65 years||33 (76.7%)||29 (76.3%)|
|Gleason score (%)|
|≤7||5 (11.6%)||2 (5.2%)|
|8–10||35 (81.4%)||32 (84.2%)|
|Not applicable||3 (7.0%)||4 (10.5%)|
|0||16 (37.2%)||18 (47.4%)|
|1||24 (55.8%)||18 (47.4%)|
|2||3 (7.0%)||2 (5.3%)|
|Serum baseline PSA|
|Median (range)||158.9 (4.1–5314)||197 (27–2182)|
|<20 ng/mL||4 (9.4%)||0|
|≥20 ng/mL||39 (90.7%)||38 (100%)|
|Extent of disease|
|Bone metastases only||15 (34.9%)||15 (39.5%)|
|Visceral metastases only||2 (4.7%)||3 (7.9%)|
|Bone and visceral metastases||26 (60.5%)||20 (52.6%)|
|Liver metastases||8 (18.6%)||0|
|Lung metastases||2 (4.7%)||2 (5.3%)|
|Lymph node metastases||23 (53.5%)||21 (55.3%)|
|Prior docetaxel lines|
|1||39 (90.7%)||36 (94.7%)|
|2||4 (9.3%)||1 (2.6%)|
|PSA response to docetaxel|
|Responder||24 (55.8%)||22 (57.9%)|
|Non-responder||19 (44.2%)||16 (42.1%)|
|Bisphosphonate at baseline|
|Yes||20 (46.5%)||12 (31.6%)|
|No||23 (53.5%)||26 (68.4%)|
|Corticosteroid at baseline|
|Yes||22 (51.2%)||16 (42.1%)|
|No||21 (48.8%)||22 (57.9%)|
|Pain score at baselinea|
|<2||19 (44.2%)||15 (39.5%)|
|≥2||21 (48.8%)||22 (57.9%)|
|Target and non-target lesions||25 (58.1%)||19 (50.0%)|
|Target lesions (only)||1 (2.3%)||2 (5.3%)|
|Non-target lesions (only)||17 (39.5%)||17 (44.7%)|
PSA response to the last prior docetaxel line was achieved by 56% and 58% of patients in arms A and B, respectively. The median duration of treatment was 8.4 (range 0.14–37.14) weeks in arm A and 9.93 (range 0.14–132.14) weeks in arm B, with a median dose intensity of 184.8 mg/m2/week and 215.2 mg/m2/week, respectively. Treatment modifications, mainly dose delays and omissions, were more frequent in arm A (74.3%) than in arm B (36%) (Table 2). The main reason for dose delays and reductions was grade ≥3 neutropenia.
|Arm A (N = 43)||Arm B (N = 38)|
|Median (range)||2 (1–8)||3 (1–33)|
|Treatment duration (weeks)|
|Median (range)||8.43 (0.14–37.14)||9.93 (0.14–132.14)|
|Dose intensity (mg/m2/week)|
|Intended dose intensity||247.50||250.00|
|Median (range)||184.81 (76.70–251.04)||215.15 (124.68–257.29)|
|Relative dose intensity||74.67%||86.06%|
|Cumulative dose (mg/m2)|
|Median (range)||1970.95 (306.8–8076.5)||2620.86 (498.7–32 660.1)|
|Number of patients||34||25|
|Number of cycles||71||52|
|Number of events||92||58|
|Reasons for delay|
|Number of patients||15||7|
|Number of cycles||21||7|
|Number of events||22||7|
|Reasons for omission|
|Number of patients||4||4|
|Number of cycles||4||4|
|Number of events||4||4|
|Reasons for reduction|
Of the 60 evaluable patients, two patients, one in each arm, had a confirmed PSA response, lasting 8.3 weeks and 33.6 weeks for the patient in arm A and the patient in arm B, respectively (Table 3). Both patients with a PSA response also had a PSA response during prior docetaxel chemotherapy. The two study groups did not meet the criteria for continuation into the second part of the study.
|Arm A (N = 43)||Arm B (N = 38)|
|>50% PSA response||1 (3.2%)||1 (3.4%)|
|>30% and <50% PSA response|
|Unconfirmed||1 (3.2%)||2 (6.9%)|
|Stable disease (overall)||8 (18.6%)||13 (34.2%)|
|Stable disease ≥6 months||4 (9.3%)||7 (18.4%)|
|Progressive disease||23 (53.5%)||17 (44.7%)|
|Not evaluable||12 (27.9%)||8 (21.1%)|
|Clinical benefit assessment|
|Pain and analgesic score||4 (14.3%)||3 (12.5%)|
|Pain score improvement (only)||1 (3.6%)||1 (4.2%)|
There were no objective tumour responses according to modified RECIST and PSA Working Group criteria. The best overall response was disease stabilization in 8/43 (18.6%) patients in arm A and 13/38 (34.2%) in arm B. Clinically relevant disease stabilizations (lasting ≥6 months) were reported in 4/43 (9.3%) patients in arm A and in 7/38 (18.4%) in arm B (Table 3). Three patients, all in arm B, had disease stabilization lasting ≥20 months.
Fifty-two (64.2%) patients were evaluable for clinical benefit. Six out of 28 (21.4%) patients in arm A and 4/24 (16.7%) patients in arm B had a clinical benefit on treatment (Table 3).
At the time of data analysis 30/43 (86.1%) patients in arm A and 26/38 (92.1%) patients in arm B had investigator-determined progressive disease. Median PFS was 12.1 weeks (95% CI 10.9–15.1) for arm A and 12.0 weeks (95% CI 10.3–17.0) for arm B (Fig. 2).
Safety and Tolerability
Both schedules showed acceptable toxicity. In all, 93% of all patients experienced at least one drug-related adverse event. The most frequent grade ≥3 drug-related adverse events were neutropenia in 22 patients (16 arm A; six arm B), fatigue in five patients (four arm A; one arm B) and neutropenic fever (two patients in each arm) (Table 4). Irrespective of the treatment arm, the most common drug-related adverse events for all grades involved gastrointestinal disorders (61.7%), general disorders and administration site conditions (60.5%) and blood and lymphatic system disorders (50.6%) (Table 4). No drug-related deaths were reported. One patient died on study due to pneumonia, unlikely to be related to the study drug.
|Event||CTC grade||Arm A (N = 43)||Arm B (N = 38)||Total (N = 81)|
|Abdominal pain NOS||1–4||3||7.0||4||10.5||7||8.6|
|Alanine aminotransferase increased||1–4||3||7.0||1||2.6||4||4.9|
|Mucosal inflammation NOS||1–4||2||4.7||2||5.3||4||4.9|
|Oral fungal infection NOS||1–4||2||4.7||2||5.3||4||4.9|
|Peripheral sensory neuropathy||1–4||3||7.0||1||2.6||4||4.9|
Aurora kinases are frequently overexpressed in prostate cancer and therefore these proteins are an attractive target for treatment in patients with CRPC . Danusertib showed in vivo antitumour activity in prostate cancer models. This randomized phase II study demonstrated that danusertib has minimal single agent activity in patients with docetaxel-refractory CRPC. Due to the modest efficacy, the trial did not meet the criteria to enter the second stage of the study. Both schedules demonstrated a manageable toxicity profile consistent with earlier clinical trials.
While PSA response was observed in only two patients, 11 patients (13.6%) had sustained stable disease lasting ≥6 months. In the absence of a placebo control arm, it may be difficult to discriminate whether a stable disease is attributable to the treatment efficacy or an indolent behaviour of the disease. However, all evaluable patients had documented disease progression before entering the trial. As with other molecular targeted therapies, the key question to be addressed will be concerned to identify the subset of patients with the highest probability of responding to danusertib. A predictive biomarker that can be used for this purpose has not yet been identified.
As discussed, this study enrolled an unselected population with progressive metastatic CRPC after docetaxel. It has recently been demonstrated that a previously under-recognized sub-population of prostate cancer, termed neuroendocrine prostate cancer (NEPC) or anaplastic prostate cancer, demonstrates marked AURKA amplification compared with prostatic adenocarcinoma . Aurora kinase A protein is also overexpressed in NEPC compared with adenocarcinoma. Both in vitro and in vivo models support the treatment of NEPC with danusertib. While clinical use of aurora kinase inhibitors has not demonstrated overwhelming success, it is possible that by selecting a more optimal population with NEPC would yield more promising results. It has been estimated that up to 25% of men with chemotherapy-naive metastatic prostate cancer harbour clinical features of NEPC  and treatment with hormonal therapy may induce neuroendocrine differentiation [22, 23]. While it would have been interesting to retrospectively assess responders and those with prolonged stable disease, we do not have data on NEPC features in this study.
There are a few limitations to the present study that should be considered. There was a discrepancy between the evaluable patients and the randomized patients. Exclusions from the evaluable patient population were in large part due to one or no PSA assessment on treatment, which reflected the high rates of early discontinuation of the study treatment due to rapid disease progression and clinical deterioration of patient's progression during or after docetaxel chemotherapy. The potential impact of these early terminations on the efficacy and safety endpoints should be considered.
Assessing the activity of targeted therapies in patients with CRPC is challenging given the preponderance of bone metastases. In 2008, the Prostate Cancer Clinical Trials Working Group 2 consensus redefined consensus criteria for early-phase clinical trial endpoints which were only partly incorporated in this study. The application of the different criteria for progressive disease for patients without measurable disease could have led to different outcomes in our study.
Another possible confounder is the use and reliance on PSA response as the primary endpoint of response . Although an important and useful tumour marker, changes in PSA do not always correlate with regression of tumour and clinical benefit . Interpretation of PSA data is even more obscured with the use of targeted agents, some of which result in discrepancy between PSA response and clinical benefit [26, 27]. The limitations of PSA as the primary indicator of response have to be considered in interpreting the results of our study.
In conclusion, in spite of minimal response in terms of PSA decrease, the sizeable number of durable disease stabilizations observed may warrant further investigation in this patient population. Development of specific biomarkers predictive for response may enable patients to be selected with potential benefit of danusertib. Further assessment of this aurora kinase inhibitor in CRPC is not indicated from the results of this study.
Conflict of Interest
This work was supported by Nerviano Medical Sciences S.r.l., Nerviano (MI), Italy. R. de Wit's institution has received data management support from Nerviano Medical Sciences S.r.l. G. Jannuzzo, M. Mariani and A. Petroccione are employees of Nerviano Medical Sciences S.r.l. They have no leadership position, stock ownership, research funding, expert testimony or other remuneration disclosures. The other authors have no conflict of interest.
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