Mechanism of action and clinical activity of tasquinimod in castrate-resistant prostate cancer

Figures & data

Figure 1 Current therapeutic options for patients with metastatic CRPC.

Abbreviation: CRPC, castrate-resistant prostate cancer.

Table 1 Treatment agents approved in CRPC

Agent	Brand name	Mechanism of action	Indication	Year approved	Pivotal Phase III trial
Sipuleucel-T^Citation12	Provenge	Immunotherapy that stimulates T cell response against PAP	Chemotherapy naïve minimally symptomatic mCRPC	2010	IMPACT
Cabazitaxel^Citation13	Jevtana	Chemotherapy inhibiting microtubule depolymerization	Post-docetaxel symptomatic mCRPC	2010	TROPIC
Denosumab^Citation14	Xgeva	Inhibits RANK ligand	mCRPC with bone metastasis	2010	Prostate cancer SRE study
Abiraterone^Citation15	Zytiga	Inhibits CYP 17	Post-docetaxel symptomatic mCRPC	2011	COU-AA 301
Abiraterone^Citation10	Zytiga	Inhibits CYP 17	Chemotherapy naïve minimally symptomatic mCRPC	2012	COU-AA 302
Enzalutamide^Citation9	Xtandi	Inhibits androgen receptor	Post-docetaxel symptomatic mCRPC	2012	AFFIRM
Radium Ra223 chloride^Citation11	Xofigo	Emits alpha particles to destroy metastatic bone cells	mCRPC with bone metastasis	2013	ALSYMPCA

Abbreviations: CRPC, castrate-resistant prostate cancer; mCRPC, metastatic CRPC; CYP, cytochrome P450; PAP, prostatic acid phosphatase; RANK, receptor activator of nuclear factor kappa-B.

Figure 2 Chemical structure of tasquinimod.

Figure 3 Mechanism of action of tasquinimod.

Abbreviations: HIF α, hypoxia inducing factor α; HDAC, histone deacetylase; VEGF, vascular endothelial growth factor; SDF-1, stromal derived factor-1; CXCR 4, C-X-C chemokine receptor 4; LOX, lysyl oxidase; TSP, thrombospondin; TAM, tumor associated macrophages; ADAMTS 1, a disintegrin and metalloproteinase with thrombospondin motifs 1; MDSC, myeloid derived suppressor cells; TLR, Toll-like receptor; RAGE, receptor for advanced glycation end products; NCOR, nuclear receptor co-repressor; BMDVMC, bone marrow derived vascular modulatory cells.

Table 2 Potential target proteins/molecules modulated by tasquinimod

Potential target proteins/molecules in CPRC	Level in CPRC	Change in levels in response to tasquinimod
Thrombospondin-1	Low	Increased
Vascular endothelial growth factor	High	Decreased
Fibroblast growth factor	High	Decreased
Hypoxia induced factor-1α protein	High	Decreased
Androgen receptor protein	High	Decreased
Stromal derived factor-1	High	Decreased
Lysyl oxidase	High	Decreased

Abbreviation: CRPC, castrate-resistant prostate cancer.

Table 3 Summary of published early phase trials of tasquinimod in CRPC

Study	Bratt et al^Citation22	Pili et al^Citation23
Phase	I	II
Patients (n)	32	206
Tumors	Asymptomatic CRPC with PSA recurrence and no prior chemotherapy	Minimally symptomatic CRPC with radiologically confirmed metastatic disease and no prior chemotherapy
Toxicities	Sinus tachycardia, asymptomatic elevation in amylase	G3/4: increased pancreatic enzymes, musculoskeletal pain, fatigue
Pharmacokinetics	Long elimination half-life (t1/2 40±16 hours), a low oral clearance (mean CL 0.28 L/h), low oral volume of distribution (Vdmean = 15 L)	Low oral clearance 0.19 L/h with 0.5 mg daily dose, 0.22 L/h with 1 mg daily dose; Vd =5.9 L
Anti-tumor effects	Time to PSA progression 19 weeks	PFS 7.6 versus 3.3 months; stable disease (SD) 52% versus 31%; patients with tumor size reduction 29% versus 16%
Recommended dose	1.0 mg per day	1.0 mg per day
Reference	^Citation22	^Citation23

Notes: In the Phase II study, the results are reported as median time to PSA progression (>25%) of 19 weeks. A serum PSA decline of ≥50% was noted in two patients. In all, 18 patients had prolonged PSA doubling time while on study, and in five patients PSA doubling time was shortened. Only 3 out of 15 patients developed new bone lesions. No patient in the trial developed tumor-related pain requiring treatment with opioid drugs. Also, patients who were treated with tasquinimod responded with a decrease in serum LDH levels. At 4 months, mean decrease in LDH in tasquinimod-treated patients was about 20% as compared with baseline.

Abbreviations: CRPC, castrate-resistant prostate cancer; LDH, lactate dehydrogenase; PFS, progression-free survival; PSA, prostate-specific antigen; Vd, volume of distribution; CL, clearance.

Figure 4 Schema for current tasquinimod Phase III study.

Abbreviation: CRPC, castrate-resistant prostate cancer.

Table 4 Ongoing trials involving tasquinimod in prostate cancer

Study	NCT 01234311^Citation57	NCT 01732549^Citation58	NCT 01513733^Citation55
Phase	III	II	I
Design	Randomized 2:1, double-blind, placebo-controlled study	Randomized, double-blind, placebo-controlled study	Non-randomized, open-label, single-arm study
Status	Ongoing, not recruiting participants	Ongoing, actively recruiting participants	Ongoing, actively recruiting participants
Expected enrolled patients (n)	1,200	140	32
Study arms	Tasquinimod versus placebo	Tasquinimod versus placebo	Tasquinimod + cabazitaxel
Disease characteristics	Chemotherapy naïve metastatic CRPC, asymptomatic to minimally symptomatic	Metastatic CRPC post-docetaxel treatment – with or without symptoms	Metastatic CRPC with prior docetaxel treatment – with or without symptoms
Setting	Treatment of progressive disease	Maintenance of stable disease post-docetaxel treatment	Treatment of progressive disease
Primary endpoint	Radiological PFS	Radiological PFS	Measurement of recommended dose of tasquinimod in combination with cabazitaxel
Secondary endpoint	OS	OS, symptomatic PFS	Radiological PFS

Abbreviations: CRPC, castrate-resistant prostate cancer; PFS, progression-free survival.

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