New Emerging Treatments
Despite these advances, the
median survival in the first-line setting of mCRPC is approximately 20 months,
and in the postdocetaxel setting is about 15 months. The modest benefits
conferred to these recently approved agents, means new tolerable drugs are
necessary to make future gains. Promising new therapies include hormonal
agents, as well as other immunotherapeutics and antiprostate-specific membrane
antigen therapies are in advanced stages of clinical development.
Some of
these trials incorporating molecular analyses are ongoing better understand
tumor biology, and to identify and evaluate new biomarkers. Nowadays, OS is the
only accepted end point for regulatory purposes in Phase III trials. To
compensate, several ongoing Phase III trials have incorporated biomarkers as
circulating tumor cells (CTCs) into their trial design in order to prospectively
evaluate CTCs as surrogate of response and survival. Isolation of CTCs based on
epithelial surface markers and quantification using the Cell Search platform
was cleared through the FDA in 2008. This was based in a study which
demonstrated that patients with a CTC count >5 detected in 7.5 ml blood had
a significantly lower OS compared to patients with CTC <5.
There
are concerns that ongoing Phase III trials may be contaminated if patients go
off study treatment to start one of the newly approved agents or take the agent
subsequently. These realities make clinical trial design more challenging than
ever. We have summarized the most promising and encouraging new drugs in Phase
III studies below.
TAK-700 (Orteronel)
TAK-700
is a reversible CYP17 inhibitor with preferential inhibition of 17,20-lyase
over 17-hydroxylase activity. This selective inhibition may in theory reduce
the need for corticosteroid supplementation. However, early data suggest that
TAK-700 has similar response profiles as abiraterone and steroid support is
needed to avoid tocixicity.[49] The most common adverse events were
fatigue, nausea and constipation. Two randomized Phase III studies of TAK-700
and prednisone versus placebo and prednisone are underway that include patients
with chemotherapy-naive and docetaxel-refractory mCRPC, respectively
(ClinicalTrials.gov identifiers: NCT01193244 and NCT01193257).[101] However, to date, we have no data from
either of these Phase III trials by which to judge its efficacy. Recently, the
Southwest Oncology Group has initiated a new, randomized, double-blind,
multicenter, Phase III trial designed to compare androgen deprivation therapy
(ADT) + bicalutamide (Casodex) to ADT + the investigational drug TAK-700 in men
newly diagnosed with metastatic, hormone-sensitive prostate cancer
(ClinicalTrials.gov identifier: NCT01809691).[101]
