POTENTIAL ROLE OF NOVEL AGENTS AND COMBINATIONS IN OVERCOMING CHEMORESISTANCE

Combinations of chemotherapy and antiandrogen drugs

A multipronged strategy is necessary to overcome chemoresistance. One rational strategy is to investigate combinations of chemotherapy with antiandrogen drugs, because both classes of agents are known to yield survival benefits as single agents. Phase I trials have already demonstrated the feasibility of combining cabazitaxel 25 mg/m2 with abiraterone–prednisone.107 However, in the trial combining cabazitaxel 25 mg/m2 and abiraterone–prednisone, seven patients (25.9%) required dose reduction of cabazitaxel due to toxicities, but all patients received ≥80% of the planned dose intensity.107 The combination of cabazitaxel 25 mg/m2 (with routine PEG-G-CSF) and enzalutamide is being evaluated in a Phase I trial (NCT02522715). Notably, the combination of enzalutamide and docetaxel is feasible and safe; indeed, the PRESIDE Phase III trial is comparing continued enzalutamide plus docetaxel vs. docetaxel after disease progression on enzalutamide alone.108 Furthermore, enzalutamide, abiraterone, and prednisone were combined in full single-agent doses, and Phase III evaluation of this combination is ongoing.109 No pharmacokinetic interactions have been seen, and toxicities have been manageable with all of these combinations. The combination of prednisone, abiraterone, cabazitaxel, and enzalutamide as first-line therapy for mCRPC will be evaluated in a planned Phase I trial. This trial will allow prior docetaxel for castration-sensitive disease.


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Combination of chemotherapy with novel biologic agents

The combination of docetaxel with novel agents has heretofore been unsuccessful in unselected patients. Phase III trials attempting to build on a template of docetaxel by combining with bevacizumab, aflibercept, DN101 (vitamin D analog), GVAX, dasatinib, atrasentan, lenalidomide, and custirsen have all been disappointing with no increments.110–115 Additionally, compromising the delivery of docetaxel owing to the added toxicities of combinations appeared to harm survival.114 Hence, the development of docetaxel plus biologic agent combinations must proceed cautiously and be guided by rational patient selection. An ongoing Phase III trial is evaluating the role of combining DCVAC, an autologous dendritic cell-based vaccine (pulsed with killed prostate cancer cell lines), with docetaxel-based chemotherapy as first-line therapy for mCRPC.

Novel agents for single-agent therapy

Novel agents may also be active as single agents following progression on chemotherapy and some of the ongoing trials in the chemoresistant setting have been outlined in Table 1. PARP inhibitors appear particularly promising in this regard. A Phase II trial enrolling 50 patients with mCRPC were treated with olaparib.81 These patients were heavily pretreated and all had received prior docetaxel, 49 had received abiraterone or enzalutamide, and 29 had received cabazitaxel. Sixteen of 49 (33%) evaluable patients had a response defined by measurable tumor regression, ≥50% PSA decline, or reduction in circulating tumor cell count. Of the 16 patients with alterations in DNA repair genes – BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK2 – 14 (88%) had a response to olaparib, including all seven patients with BRCA2 loss and four of five with ATM aberrations. Toxicities were manageable and consistent with previous olaparaib trials. A phase III trial is being planned.

(To view a larger version of Table 1, click here.)

BTK120 (Bruton tyrosine kinase 120), an inhibitor currently in open-label, single-arm Phase II clinical trial (NCT01385293) for mCRPC, progressed on previous therapies including cytotoxic agents. BI-836845 is a human monoclonal immunoglobulin (Ig)-G lambda antibody against insulin-like growth factor (IGF)-1 and IGF2, which is implicated in inhibiting apoptosis. In a Phase Ib/II trial, BI-836845 in combination with enzalutamide is being compared with enzalutamide alone in patients who have progressed on docetaxel and abiraterone. Monoamine oxidase A (MAO-A) is expressed commonly in high-grade prostate cancer and is implicated in tumor survival and metastases by EMT and angiogenesis. Phenelzine is a MAO-A inhibitor and is being studied in a Phase II trial in combination with docetaxel in patients who have progressed on docetaxel. One randomized Phase II trial is evaluating ADT with or without palbociclib, a cyclin-dependent kinase 4/6 inhibitor, for mCSPC and intact Retinoblastoma (RB). Palbociclib may potentially warrant evaluation even in postchemotherapy patients, considering the continued relevance of dependence on the androgen axis and resistance to antiandrogen drugs even after chemotherapy. The AURKA gene appears to be involved in neuroendocrine transformation, suggesting that aurora kinase inhibitors, such as MLN8237, may be active in this setting.116,117

Several novel second- and third-generation antiandrogen agents are undergoing Phase III evaluation (eg, ODM201, ARN509, galeterone, and VT464), although these trials do not specifically address chemoresistance because these trials have enrolled chemotherapy-naive patients. An extensive discussion of these agents is therefore beyond the scope of this review.

Immunotherapy was dealt a setback in the context of mCRPC when two Phase III trials evaluating ipilimumab, a cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitor, in the pre- and post-docetaxel settings did not extend OS.118 Moreover, programmed death (PD)-1 inhibitors preliminarily do not appear to have robust activity in unselected patients with advanced prostate cancer.119 Interestingly, sipuleucel-T upregulates PD-1-expressing T-cells when administered as a neoadjuvant therapy for localized disease and preliminary evidence for clinical activity of pembrolizumab in enzalutamide-resistant patients, suggesting a role for PD-1 inhibitors in selected patients.120,121 Indeed, one phase II trial is evaluating pembrolizumab in men with tumor PD-L1 expressing or non-expressing mCRPC previously treated with docetaxel (Keynote-199). Additionally, targeting angiogenesis has not yielded benefits using either the combination strategy with docetaxel (bevacizumab and aflibercept) or postdocetaxel therapy with sunitinib plus prednisone or cabozantinib.110,122–124