Unraveling the molecular make up of cancer cells has resulted in the successful development of specific targeted therapies directed at particular molecular pathways. Studies involving imatinib for CML and GIST, trastuzumab for HER-2 positive breast cancer, crizotinib for ALK-mutated lung cancer, and vemurafenib for BRAF-mutated advanced melanoma have all confirmed the significance and feasibility of targeted therapy . Considerable efforts have been made in searching for such targets for prostate cancer patients. Our understanding of the biologic and molecular driving force of prostate cancer growth and progression in the past few years have resulted in investigations of numerous novel targeted therapies, including androgen receptor (AR) targeting agents, tyrosine kinase inhibitors (TKIs), antiangiogenic agents, endothelin receptor antagonists, anti-apoptotic protein inhibitors and proteasome inhibitors [8–10]. Many of them have either received FDA approval or moved to the frontline of late stage development based on improvement of soft intermediate surrogate markers in small phase I/II trials. As bone metastasis is common in patients with mCRPC, agents targeting the bone microenvironment have been successful not only in the prevention of skeletal-related events in men with bone metastases from mCRPC, such as with denosumab and radium-223, but also in improving survival, such as with radium-223 [11, 12].
The progression of mCRPC can occur as a result of AR activation despite low levels of androgens. Numerous molecular and genetic aberrations have been postulated to be responsible for gain-of-function changes in the AR signaling pathway under androgen deprivation. This includes intratumoral androgen synthesis, AR protein overexpression, AR gene amplification or point mutations, constitutively active truncated AR splice variants, disturbance of AR-coactivator-corepressor complex, and ligand-independent AR activation by kinase cross-talk [8, 13]. Patients who failed primary and/or secondary hormonal therapies are still candidates for more potent novel hormonal agents. AA, a specific inhibitor of the key androgen synthesis enzyme CYP17, and MDV3100, a second generation antiandrogen, represent two such novel therapies targeting the androgen signaling axis in mCRPC. In the recent phase III trial of AA (COU-AA-301) , a 35% reduction in the risk of death (HR = 0.65; p < 0.0001) and a 36% increase in median survival (14.8 vs. 10.9 months) were observed in patients treated with AA plus prednisone, compared with patients who received placebo plus prednisone. Encouraging antitumor activity was also recorded in a multicenter phase I/II study of MDV3100 with 56% PSA response and 22% response in soft tissue diseases , A randomized, double-blind, multinational phase III trial (AFFIRM), comparing MDV3100 with placebo in mCRPC patients previously treated with docetaxel, was terminated early due to a 4.8 months absolute survival advantage (18.4 vs. 13.6 months) per interim analysis .
On the other hand, zibotentan, an endothelin A receptor antagonist blocking endothelin-mediated activation of multiple signaling transduction pathways , showed strong inhibition of prostate cancer cell proliferation and delayed progression of bone metastases in preclinical studies . Phase II data demonstrated a statistically significant improvement in overall survival (OS) for patients treated with zibotentan . Interestingly, the study did not meet its primary endpoint of time to progression. Moreover, at the final analysis (median follow-up of 22 months), the absolute OS benefit diminished down to 3.6 months from 7.2 months. Based on the initial OS benefit, an expanded phase III program was launched and included three trials (ENTHUSE M0, ENTHUSE M1, and ENTHUSE M1c) in disease ranging from non-metastatic CRPC (M0) to mCRPC (M1 and M1c), evaluating either single-agent zibotentan (M0 and M1) or in combination with docetaxel (M1c) . However, recent analysis of M1 showed that the study failed to meet its primary endpoint of OS . M0 was also terminated following an early efficacy review indicating that zibotentan monotherapy was unlikely to meet its primary efficacy endpoints. Whether targeting the endothelin axis in prostate cancer is a valid approach remains an open question and results from M1c are eagerly awaited.
Similar disappointing results were reported that led to the termination of the late-stage trial of sunitinib, an antiangiogenic TKI, in combination with prednisone as second-line therapy for mCRPC patients due to the lack of OS prolongation, despite an improvement in progression-free survival (PFS) (5.6 vs. 3.7 months; HR = 0.74; P = .0077) . The initiation of this phase III trial was based on the modest anti-tumor activity of sunitinib in two phase II trials [23, 24]. One trial showed 6% prostate-specific antigen (PSA) response rate and only one out of 29 evaluable patients manifested as partial response radiographically at week 12 . Some discordance of PSA elevation with radiographic response was observed and considered consistent with PSA dynamics under the unique influence of TKIs, as previously established in a phase II trial of sorafenib in mCRPC . Another phase II trial reported weak antitumor activity with 12.1% PSA response rate and 11.1% radiographic response with single-agent sunitinib . Yet a large phase III trial was implemented since 2008 and has proved to be fruitless. Both examples demonstrate the need to be more selective of agents to bring forward to be tested in the phase III setting.
While recognizing the essential role of early clinical trials in enhancing our understanding of disease biology, we must be conscious about the limitations in interpreting results owing to insufficient sample size, unreliable surrogate markers, or suboptimal outcome measures. Undoubtedly, such trials are required to facilitate efficient screening for active compounds for further clinical development. Selecting appropriate targets for development in phase III trials and the decision to move the drug forward can be difficult at times when early trials reveal only mild clinical activity based on current, suboptimal trial designs. A more stringent and validated benchmark in assessing a meaningful clinical benefit is in enormous demand.