The Evolution of Prostate Cancer Therapy: Targeting the Androgen Receptor

Prostate cancer treatment has evolvedthrough the varying eras of therapy fromone of predominantly hormonal agentswithout much effective cytotoxic ther-apy until the use of docetaxel was foundto improve overall survival in the piv-otal TAX-327 (1) and SWOG 99-16 tri-als (2). While efforts to search for theappropriate docetaxel partner has yieldeddisappointing results with multiple PhaseIII trials showing negative results, furtherhormonal manipulation steadily gainedground upon discovery of persistent hor-monal signaling with the use of novelandrogen-biosynthesis inhibitors and anti-androgens. However, resistance to theseagents is ultimately inevitable. Increasedunderstanding of these resistance mech-anisms may help re-channeling effortstoward better reﬁnement and improve-ment of drug therapies.Prostate cancer remains the secondleading cause of death in the United States.While treatment for early-stage low-riskprostate cancer has been largely contro-versial with the advent of the prostatespeciﬁc antigen (PSA) screening contro-versy, treatment for metastatic castration-resistant prostate cancer (mCRPC) hasevolved with great strides in the pastdecade, though remains incurable to thisday. Docetaxel as a treatment for mCRPCbrought about improvement in overall sur-vival (1). To date, no appropriate doc-etaxel partner has been found to be ben-eﬁcial. However, the utility of androgentargeted signaling quickly gained groundwith the discovery of the relevance ofandrogen receptor (AR) targeting longafter failure from androgen deprivationtherapy (3). This brought about the dis-covery and subsequent approval of bothabiraterone acetate (4, 5) and enzalu-tamide (6, 7) in both the post-docetaxeland pre-docetaxel space. While target-ing androgen-signaling to date makes forone of the most attractive approachesin mCRPC therapy, several challengesremain.The AR is a 110-kDa steroid recep-tor encoded by the gene located in Xq11-12 in the same family of nuclear hor-mone receptors as the estrogen, proges-terone, and glucocorticoid receptors (8).The AR functions as a “lineage oncogene”of which prostate tumors become habitu-ally addicted to (9). Conversely,severalAR-pathway genes are down-regulated uponprogression from a low-grade to high-grade prostate cancer or in the develop-ment of metastases (10). Despite targetingthe AR pathway using more contemporarydrugs with abiraterone or enzalutamide, itis now increasingly recognized that resis-tance patterns are born at the cellular level,with ligand independentAR activation,ARmutation, intratumoral androgen synthe-sis, increased AR mRNA expression, andAR maintenance by heat shock proteinsand AR structural alterations includingacquisition of splice variants all playing arole in resistance (11). Given the inevitablenotion of resistance,efforts toward not justsequencing, but combining these agentsoffer exciting insights and opportunitiesfor treatment. For instance, TOK-001,also known as galeterone, is a rationallydesigned compound that has triple mech-anism of action that includes inhibition ofCYP17A1 enzyme thereby blocking andro-gen synthesis, with preferential lyase overhydroxylase inhibition, AR inhibition byantagonizing testosterone binding to theAR, which prevents binding of syntheticandrogens to both mutant and wild-typeAR, and ﬁnally, decreasing the amount ofAR through degradation of the AR pro-tein. These unique mechanisms of actionare thought to be a possible promisingagent for the treatment of CRPC (12).Thus, far, early Phase I testing (ARMOR 1)demonstrating a minimal side effect pro-ﬁle has led to a Phase II trial (ARMOR2) evaluating efﬁcacy by means of PSAresponse(NCT01709734).WhileTOK-001and other promising drugs such as ARN-509 are in the pipeline (13), there remainsa concern of whether the clinical trial end-point that we are accustomed to that ofoverall survival is the most appropriateendpoint. To illustrate this point, results ofalyaseinhibitorTAK-700ororteronelhavebeen presented in both the post-docetaxeland pre-docetaxel setting. While the eli-gibility criteria and study design appearscomparable to contemporary clinical tri-als such as the COU-AA-301 and COU-AA-302 as well as AFFIRM and PREVAILtrials with abiraterone and enzalutamide,respectively, the TAK-700 trials ELM-PC5and ELM-PC4 were disappointingly nega-tive. This raises a concern since this drug,along with a multitude of other drugs,maynot necessarily be clinically inferior, butincreasingly difﬁcult to prove superiorityor even equivalency given the landscapeof drugs currently approved that has beenshown to improve overall survival.Addressing the issue of resistance is ofrelevant importance given the notion thatall CRPC tumors will fail treatment even-tually. Provocative ﬁndings show gain-of-function mutation in 3b-hydroxysteroiddehydrogenase type 1 (3bHSD1) enzymethat renders an alternative pathway toresistance by inhibition of degradation