Tasquinimod: A Novel Angiogenesis Inhibitor–Development in Prostate Cancer
Saby George • Roberto Pili

Published online: 20 January 2013
Ⓒ Springer Science+Business Media New York 2013

Abstract Castration resistant prostate cancer (CRPC) treat- ment has been revolutionized over the past few years by the approval of novel therapies including cabazitaxel, sipuleucel-T, abiraterone and enzalutamide. Though andro- gen deprivation and chemotherapy remain the main thera- peutic approaches for this disease, a series of targeted agents is also in development for the treatment of CRPC. Tasquinimod is a quinolone-3-carboxamide with antiangio- genic and antitumor activity in preclinical models of pros- tate cancer. A recent Phase II trial with this agent has demonstrated a significant clinical activity in asymptomatic or minimally symptomatic, chemotherapy-naïve, CRPC patients. A confirmatory Phase III trial of tasquinimod in prostate cancer is underway. Because of its antiangiogenic and immunomodulatory properties tasquinimod represents a novel targeted therapy with a unique mechanism of action.

Keywords Castration resistant prostate cancer (CRPC) . Angiogenesis inhibitor . Adenocarcinoma of prostate . Targeted therapy

Introduction

Prostate cancer is the most common cancer affecting males and is the second leading cause of cancer death in males [1]. Recent years have witnessed the development and approval of abiraterone (androgen synthesis inhibitor) and enzaluta- mide (antiandrogen), as second-line hormonal therapies in
the post-docetaxel setting of CRPC patients, based on pro- longed survival [2, 3]. Sipuleucel-T is also the first immu- notherapy approved by the FDA for cancer therapy and has been shown to prolong the survival of CRPC patients with low volume disease and minimal symptoms [4]. Cabazitaxel is a second line chemotherapeutic agent that induces clinical benefit in CRPC patients following first-line chemotherapy with docetaxel [5].
CRPC represents a broad spectrum of biological pheno- types where the response to subsequent androgen depriva- tion therapies is variable but common both before and after the treatment with standard first-line chemotherapy treat- ment with docetaxel. The development of biological thera- pies (i.e. antiangiogenics) as either single agents or in combination with chemotherapy has been disappointing [7, 8•]. Testing “non cytotoxic” agents in advanced CRPC is challenging. The pre-docetaxel setting is generally associat- ed with low burden, asymptomatic or minimally symptom- atic disease and perhaps represents a more suitable opportunity to demonstrate clinical benefit from targeted therapies.

Tasquinimod: A Novel Angiogenesis Inhibitor

Tasquinimod is a quinolone-3-carboxamide with preclinical antiangiogenic properties and antitumor activity in human prostate cancer models [8•, 9]. Interestingly, tasquinimod has been found to be an inhibitor of S100A9, a receptor

expressed on stroma/immune cells including myeloid de-

S. George : R. Pili (*)
Genitorurinary Program, Roswell Park Cancer Institute, Elm & Carlton Streets,
Buffalo, NY 14263, USA
e-mail: [email protected]
S. George
e-mail: [email protected]
rived suppressor cells (MDSC) [10]. MDSC have unique properties in suppressing anticancer immune responses and promoting tumor angiogenesis [11]. Preclinical data sup- ports the ability of tasquinimod to inhibit tumor angiogen- esis, hypoxic response, and to downregulate various hypoxia inducible genes. Promising animal testing has led

to clinical testing. A Phase I trial has demonstrated safety and tolerability of tasquinimod and the results from a Phase II randomized placebo control trial in CRPC patients were recently reported [12, 13••].

Antiangiogenic Properties of Tasquinimod

Preclinical testing of tasquinimod has demonstrated its ability to inhibit angiogenesis with a unique mechanism of action. The antiangiogenic effects are not mediated directly via the VEGF signaling pathway. Tasquinimod has been shown to inhibit HIF-1α which is a transcriptional regulator of various proangiogenic genes [8•, 9]. The inhibition of HIF-1α by tasquinimod results in down regulation of angiogenesis- related genes and inhibition of metastases [14]. A recent report suggests that HIF-1α down regulation may be mediated via the binding of tasquinimod to a class II histone deacetylase, HDAC4 (Fig. 1) [15•]. Class II HDACs have been associated with HIF-1α protein stability [16]. Tasquinimod also prevents the angiogenic rebound induced by fractionated radiation resulting in an enhanced therapeutic response of prostate can- cer xenografts [17]. Furthermore, tasquinimod has been shown to increase thrombospondin-1 (TSP-1) levels, which is an endogenous angiogenesis inhibitor [18].

Immunomodulatory Properties of Tasquinimod

Tasquinimod also has immunomodulatory effects, which ap- pear to be via its ability to bind to S100A9 and thus potentially affect MDSC functions (Fig. 1). A recent study by Li Shen et al. has shown that accumulation of MDSC occurs in two murine prostate cancer models [19]. The MDSC levels also increased with progression of disease. The study also demon- strated that the administration of tasquinimod alone has the ability to reduce the number of circulating MDSCs. When tasquinimod was combined with a survivin peptide mimetic vaccine, it enhanced immune cell-mediated cytotoxicity and improved antitumor response in a castrate-resistant prostate cancer model.

Clinical Activity of Tasquinimod

A Phase II trial of tasquinimod in CRPC patients was recently completed. This was a double-blind, placebo control study with a 2:1 randomization in asymptomatic or minimally asymptomatic CRPC patients [13••]. The eligible criteria in- cluded histologically confirmed adenocarcinoma of prostate, Karnofsky performance status of 70 % or higher, serum tes- tosterone level of <50 ng/dl, pain score of 3 or more on a scale from 1 to 10, and radiographically confirmed metastatic
disease with three consecutive rises in PSA, radiographic progression of soft tissue disease, or the development of new bone lesions on bone scan within 12 weeks prior to random- ization. Adequate liver, kidney, and marrow function were essential inclusion criteria. The major exclusion criteria includ- ed prior anti-cancer chemotherapy within 3 years, prior bev- acizumab, history of coronary artery disease or congestive heart failure. The randomization was also stratified by perfor- mance status (KPS 90 to 100 vs. KPS 70 to 80) [13••].
The treatment plan included a titration schema (starting tasquinimod dose at 0.25 mg daily for 2 weeks, then esca- lated to 0.5 mg daily for 2 weeks) up to 1 mg daily (full dose) for 6 months. Cross-over to open label tasquinimod was offered for placebo patients (at progression or at the end of 6 months) and open label continuation of tasquinimod was permitted for active treatment group, until progression. The primary endpoint of the trial was the progression-free proportion (PFP) at 6 months. Disease progression consid- ered pain, radiographic progression (RECIST 1.0 for soft tissues) and PCWG2 criteria for bone lesions [20].
Two hundred and one patients were randomized at 45 centers. The tasquinimod group included more patients with visceral metastasis, with tumor related pain, higher median baseline PSA and shorter median PSA doubling time. The primary endpoint of progression-free proportion at 6 months favored the tasquinimod arm (67 % vs. 37 %, RR 0.49, 95 % CI 0.36 to 0.67, p<0.001). The median progression free sur- vival (PFS) was 7.6 months vs. 3.3 months favoring the tasquinimod arm (HR 0.57, 95 % CI, 0.39 to 0.85, p=0.0042). For men with visceral metastasis, bone only dis- ease and lymph node only disease, the median PFS per PCWG2 criteria favored the tasquinimod group. There were 7 % vs. 0 % soft-tissue responders according to the RECIST criteria, again favoring the tasquinimod group. PSA response was 4 % in tasquinimod vs. 0 % in placebo.
Fifty-five percent of patents in the tasquinimod arm re- quired discontinuation of therapy for various reasons includ- ing toxicity. The most commonly observed adverse events in the tasquinimod arm included fatigue (29 %), nausea (27 %), constipation (25 %), vomiting (10 %), diarrhea (12 %), muscle pain (10 %), joint pain (16 %), and deep vein thrombosis (4 %). The pharmacokinetic profile of tasquinimod did not show differences across different ethnicity or hepatic function. Updated survival analysis was recently presented and has shown a survival advantage, though not statistically signifi- cant, in the tasquinimod arm (33.4 vs. 30.4 months, p=0.49) [21]. The subgroup analysis also confirmed that in the bone metastatic group there was a trend in survival advantage for the tasquinimod arm compared to the placebo (34.2 vs.
⦁ months, p=0.19). At 6 months, there were 93/134 patients in the tasquinimod arm and 25/67 placebo arm, who were progression-free. Cross-over to open label tasquinimod was offered to the placebo group patients who were progression

Fig. 1 Tasquinimod induced antiangiogenic and immunomodulatory effects

free and 17 patients who received tasquinimod, demonstrated improvement in PFS. Several correlative studies were con- ducted during this trial. Updated biomarker analysis results were recently presented at ESMO 2012 [22]. Various bio- markers were analyzed at baseline and at week 8. After 8 weeks of treatment with tasquinimod, there was a significant increase in the levels of VEGF-A, TSP-1, and RAGE. The lower levels at week 8 correlated with improved survival for VEGF-C (HR
=1.39, p=0.034), TGF-β (HR=1.31, p=0.029) and TSP-1
(HR=1.28, p=0.017) in tasquinimod treated patients only. This particular effect was particularly noticeable in patients with bone metastatic disease.
A randomized, double-blind, placebo-controlled, interna- tional Phase III clinical trial of tasquinimod is ongoing (NCT01234311) in the metastatic CRPC population with no significant pain. This trial also randomizes patients in a 2:1 ratio to tasquinimod vs. placebo. The primary objective is to confirm the effect of tasquinimod on delaying disease progression or death compared to placebo. The primary endpoint is radiological PFS, defined as the time from the date of randomization to the date of radiological progression or death. The study was powered for assessment of overall sur- vival as a key secondary endpoint and thus was planned to include 1,200 patients. This trial is currently recruiting at 237 international locations.

Future Developments

Tasquinimod is a promising agent with unique antiangio- genic and immunological properties. This agent is also
being tested in other tumors including renal cell carcinoma where antiangiogenics have shown clinical benefit. Preclinical evidence also suggests that tasquinimod has sig- nificant antitumor activity in combination with chemothera- pies [9]. A Phase I clinical trial (The CATCH prostate cancer trial) is currently being conducted to test the combination with cabazitaxel in post-docetaxel CRPC patients. Based on its potential immunomodulatory activity, there is a rationale for combining tasquinimod with immunotherapies including sipuleucel-T in prostate cancer. Furthermore, a better under- standing of the molecular determinants responsible for the biological properties of tasquinimod will implement its use not only in prostate cancer but also in other malignancies.

Conclusions

CRPC is a term that represents a heterogeneous group of patients whose disease progresses despite castrate levels of testosterone [23]. Recent developments in the treatment of this disease have led to a better understand- ing of prostate cancer biology. CRPC patients now have new drugs available that have shown incremental clini- cal benefit. Tasquinimod is an orally available antian- giogenic agent that has shown clinical activity and is under development in CRPC. Novel agents with “alter- native” mechanisms of action to androgen deprivation represent an important resource for patients with recur- rent prostate cancer. The antiangiogenic and immuno- modulatory properties of tasquinimod along with its toxicity profile makes this novel compound suitable for

rationale combination strategies in different settings of recurrent prostate cancer.

Disclosure S. George: none; R. Pili: has received research fundings from Active Biotech and is consultant for Ipsen.

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