Metastatic Castration-Resistant Prostate Cancer: Drug Resistance: Development of New Agents in CRPC

Targeting AR-associated Signaling

As CRPC remains dependent on AR-associated signaling, new agents targeting either enzymes required for androgen synthesis or the AR itself are in clinical development. These include an inhibitor of CYP17A, abiraterone acetate (hereafter abiraterone), and the second-generation oral antiandrogen MDV3100 (Medivation, San Francisco, CA, USA).

The pregnenolone derivative abiraterone is a potent and irreversible inhibitor of CYP17A, which is an enzyme that catalyzes two steps in androgen synthesis. A phase I study showed that abiraterone suppressed the production of adrenal androgens and testosterone more profoundly than ketokonazole, and no rebound phenomenon occurred at the time of progression.^[64] Two phase II clinical studies in men with docetaxel-naive prostate cancer and in men previously treated with docetaxel showed substantial efficacy of abiraterone, as measured by PSA response.^[65,66] Phase III clinical trials evaluating abiraterone in men previously treated with docetaxel and in docetaxel-naive men with no or minimally symptomatic metastatic disease have recently completed accrual (COU-AA-301 and COU-AA-302, respectively; Table 1 ).

MDV3100 is a second-generation antiandrogen diarylthiohydantoin that acts as a potent antagonist of the AR in CRPC cells, including those with overexpressed or mutated AR.^[67] MDV3100 also blocks translocation of the AR into the nucleus, recruitment of coactivators and binding of AR to DNA.^[67] a phase I/II dose-escalation study in docetaxel-naive men and in men previously treated with docetaxel demonstrated high rates of PsA response and minimal toxic effects after treatment with MDV3100.^[68] A phase III clinical trial (Affirm), which will evaluate treatment with MDV3100 in men with metastatic CRPC progressing after treatment with docetaxel is recruiting patients ( Table 1 ).

Men with CRPC will eventually have disease progression with rising PsA following treatment with abiraterone or MDV3100, most likely associated with reactivation of the AR. Possible mechanisms of resistance to these agents include (further) mutations of the AR, truncated and constitutively activated AR, synthesis of androgens via CYP17A-independent pathways, and genetic changes in CYP17A, which prevent its inhibition by abiraterone.^[69] To overcome resistance and improve the efficacy of inhibition of AR-dependent signaling, abiraterone and MDV3100 might be used in combination, and a new agent, TOK-001 (Tokai Pharmaceuticals, Cambridge, MA, USA), which inhibits both the AR and CYP17A is being evaluated in chemotherapy-naive men in a phase II clinical trial ( Table 2 ).

Although AR-dependent signaling almost always occurs in CRPC, there can be substantial heterogeneity in the intensity of this AR signaling.^[70] Cancers with lower AR activity tend to have upregulation of other pathways (for example, Src/SFK).^[70] Currently, a phase II clinical trial (ARS trial; NCT00918385) is exploring genomic-guided therapy in chemotherapy-naive men with metastatic CRPC progressing on hormonal therapy; if the genomic signature of metastases shows high AR activity men will receive the antiandrogen nilutamide, and those with low activity will receive the Src/SFK inhibitor agent dasatinib.

Targeting Proliferation and Survival Pathways

Several drugs that inhibit alternative pathways that have crosstalk with AR-dependent pathways have been or are being evaluated in clinical trials. In phase II clinical trials in men with CRCP, drugs targeting EGFR and/ or HER-2/neu (that is erlotinib, gefitinib, lapatinib and pertuzumab) did not show substantial activity either in combination with docetaxel or alone.^[71-75] Other phase II clinical trials are evaluating the anti-EGFR monoclonal antibody cetuximab in combination with chemotherapy in this population of patients ( Table 3 ). Combinations of monoclonal antibodies against IGFR-I (that is figitumumab and cixutumumab) and chemotherapy are being evaluated in randomized phase II clinical trials ( Table 2 ). Paradoxically, despite encouraging preclinical data showing that IL-6 has an important role in the development of drug resistance in CRPC, a randomized phase II clinical trial comparing a combination of a monoclonal antibody against IL-6 (CNTO-328; Centocor, Horsham, PA, USA) and mitoxantrone with mitoxantrone alone in men previously treated with docetaxel was terminated when more deaths occurred in the experimental arm than the comparator (nine versus four deaths); the majority of these deaths were due to disease progression.^[76]

When exposed to chemotherapy and other stresses cancer cells activate mechanisms that promote survival.^[33] A combination of oblimersen, an antisense oligonucleotide against Bcl-2 mRNA (which inhibits apoptosis), and docetaxel did not show better activity than docetaxel alone in a randomized phase II clinical trial.^[77] The antisense oligonucleotide custirsen, which targets the mRNA for the survival factor clusterin, showed promising activity when combined with docetaxel or mitoxantrone in men progressing on docetaxel or within 6 months of finishing docetaxel in a phase II clinical trial.^[78] A phase III clinical trial evaluating the combination of custirsen and docetaxel in men previously treated with docetaxel is open for accrual ( Table 1 ), and a trial of docetaxel and prednisone with or without added custirsen in men with chemotherapy-naive metastatic CRPC will open shortly. In addition, an antisense oligonucleotide against survivin mRNA (gataparsen sodium) and an agent targeting multiple proteins of the Bcl-2 family (AT-101; Ascenta Therapeutics, Malvern, PA, USA) are being evaluated in combination with docetaxel In phase II clinical trials ( Table 2 ).

Targeting Angiogenesis

Blocking of VEGFR signaling may lead to transient improvement in the structure and function of blood vessels in some tumors, decrease interstitial pressure and improve drug delivery and oxygen to cancer cells.^[79] Different antiangiogenic agents are under evaluation in clinical trials in combination with docetaxel. In phase II clinical trials, antiangiogenic agents, such as bevacizumab, thalidomide and sunitinib, showed activity when combined with docetaxel^[80,81] or when used alone.^[82] However, bevacizumab in combination with docetaxel and prednisone did not lead to improvement in survival of men with CRPC when compared with docetaxel and prednisone in the CALGB 90401 phase III clinical trial.^[83] The VENICE trial, which compares the more potent VEGF inhibitor aflibercept in combination with docetaxel and prednisone with docetaxel and prednisone alone completed accrual recently ( Table 1 ).

Agents that target VEGFR and several other receptor kinases are being evaluated in phase II clinical trials either in combination with docetaxel or alone ( Table 2 and Table 3 ). A phase III clinical trial (SUN 1120) evaluating sunitinib as monotherapy in men previously treated with chemotherapy is open for accrual ( Table 1 ). Lenalidomide, which is a less toxic antiangiogenic and immunomodulatory analog of thalidomide, is being evaluated in combination with docetaxel in a phase III clinical trial (MAINSAIL, Table 1 ). Antiangiogenic monoclonal antibodies targeting α_vβ₃ and a_vp₅ integrin receptors expressed on endothelial cells (for example, CNTO-95 [Centocor, Horsham, PA, USA] and etaracizumab) are also being evaluated in combination with docetaxel in randomized phase II clinical trials ( Table 2 ).

Targeting the Microenvironment

Targeting only the microenvironment (for example, osteoblasts) may not be a successful approach, as demonstrated recently by the failure of atrasentan, an E_AR antagonist, to improve survival of men with metastatic prostate cancer.^[84] The combination of docetaxel and an E_AR antagonist targets prostate cancer cells and osteoblasts and two E_AR antagonists, atrasentan and zibotentan, are undergoing evaluation in combination with docetaxel in phase III clinical trials ( Table 1 ).

Recent experience with bone-seeking radiopharmaceuticals, which have a potent effect on both metastatic prostate cancer cells and host cells within bone, is promising. A randomized phase II clinical trial in men with CRPC and bone metastases, demonstrated a significant improvement in median overall survival (27.7 months versus 16.6 months; P = 0.001) in favor of chemotherapy followed by consolidation with the β-emitting strontium (⁸⁹Sr) when compared with chemotherapy alone.^[85] A confirmatory phase III clinical trial studying consolidation with ^[89Sr after chemotherapy is ongoing ( Table 1 ). Similarly, results of phase II clinical trials evaluating the combination of the β-emitting samarium (¹⁵³Sm) and docetaxel, and the α-emitting radium (²²³Ra; alpharadin) as monotherapy showed promising results.^[86,87] A phase III clinical trial evaluating ²²³Ra in men previously treated with chemotherapy is currently recruiting patients ( Table 1 ). A conjugate of the radiopharmaceutical β-emitting lutetium (¹⁷⁷Lu) with a monoclonal antibody against prostate-specific membrane antigen (¹⁷⁷Lu-J591), which targets prostate cancer cells (not restricted to those in bone metastases) is being evaluated in a phase II clinical trial ( Table 3 ).

Other targeted agents, used either alone or in combination with docetaxel, might simultaneously target both prostate cancer cells and their microenvironment. New agents under evaluation in clinical trials include dasatinib, a Src/SFK inhibitor, in combination with docetaxel in a phase III clinical trial, and CNTO-888 (Centocor, Horsham, PA, USA), a monoclonal antibody against the chemokine CCL2, as monotherapy in a phase II clinical trial ( Table 1 , Table 2 and Table 3 ).

Evading Resistance to Taxanes

Intensification of the targeting of microtubules with the combination of docetaxel and another microtubule-targeting chemotherapeutic agent estramustine did not demonstrate benefit over docetaxel alone.^[88] Other chemotherapeutic agents, such as the DNA-damaging agents mitoxantrone and satraplatin, showed limited activity against metastatic CRPC progressing after docetaxel therapy ( Table 1 ).^[89,90]

New agents designed to inhibit cellular mechanisms of resistance to docetaxel are under evaluation. Agents that are structurally similar to docetaxel but are weaker substrates for the P-gp efflux pump have been studied. A phase III clinical trial (TROPiC), which compared cabazitaxel to mitoxantrone in men progressing after docetaxel therapy showed an improvement in median overall survival in favor of cabazitaxel (15.1 months versus 12.7 months, hazard ratio 0.70, P <0.0001)>Table 1 ),^[91] and this drug has now been approved by the FDA as second-line treatment for CRPC. Epothilones (for example, ixabepilone, patupilone and sagopilone) have shown activity in phase II clinical trials^[92] and are undergoing further evaluation. Third-generation taxanes (for example, TPI-287 [Tapestry Pharmaceuticals, Inc., CO, USA]) and targeted agents directed against the mitotic process (for example, kinesin spindle protein and the serine-threonine aurora kinase) are also being studied in phase II clinical trials in men with metastatic prostate cancer