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Mason What clinicians should want from scientists

hypothesis a lab programme which compared tissue some years, this drug was, effectively, put “back on the
from early disease with those from locally advanced shelf”, because it was not obvious what advantages it
disease would surely bear fruit? might offer compared to existing anti-androgens such
as flutamide, although the mechanism of action is
WHAT HAVE WE LEARNED FROM CLINICAL different; flutamide is a competitive blocker of the AR,
TRIALS ABOUT LIFE-THREATENING while abiraterone inhibits androgen synthesis. Part
of the reason for the clinical uncertainty was that in
PROSTATE CANCER? the late 1990s, when this decision was made, it was
not appreciated that prostate cancer cells contained
Generations of oncologists and urologists in training low levels of androgen, even in advanced cases, and
were taught that advanced prostate cancer was that they were even capable of synthesising their
characterised by a phase during which the disease own androgen [18] . Once this was recognised, there
would respond to hormone therapy of some sort, an was a new rationale for testing abiraterone in patients
observation that dates back over 70 years [13] . After a progressing after firstline ADT. This was done in two
period, which in the case of metastatic disease might pivotal randomised trials, comparing abiraterone with
have been only of the order of 18 months, the disease placebo and showing unequivocally that abiraterone
progressed, and it was perfectly reasonable to ascribe improved survival [19,20] . As well as the obvious clinical
the label “hormone resistant” to this latter phase. benefits, these studies confirmed, and extended
A “favourite” question that clinicians want to ask of the initial laboratory observations; prostate cancer
their scientific colleagues is why this should be, and growth, even in advanced cases, remains driven by
what might be the mechanism of disease progression the androgen receptor. Mutations in the AR may allow
after first line treatment with ADT. The multitude of cancer cells to respond to minutes levels of androgen,
explanations seem to fall into two categories: one in to different ligands, or even to be ligand-independent,
which some sort of acquired hormone insensitivity but at its heart, advanced prostate cancer is anything
emerges, probably as a result of additional mutations, but “hormone-resistant” - if anything, it is often “hormone
super-sensitive”. This finding drove the recent change
or other changes in key molecules such as the in nomenclature, from “hormone-resistant” to “castrate
androgen receptor [14] . An alternative possibility is that refractory”, a term which we must acknowledge is
disease progression results from the clonal expansion hated by our patients. We must also remember,
of a subgroup of cells, present at the time of the initial though, that the survival benefits in these advanced
ADT, but insensitive to treatment ab initio. Support for patients are modest- of the order of a few months’
the latter possibility comes from a randomised trial only, and that disease progression after abiraterone
conducted by the EORTC, in which patients, who were (and similarly after novel and more potent AR blockers
not fit enough to receive curative therapy, were planned such as enzalutamide) is inevitable [21,22] . The scientific
to commence long-term ADT and were randomised imperative for clinicians is to understand what other
between immediate therapy, and treatment delayed pathways co-operate with AR-mediated signalling to
until further disease progression [15] . There was no drive subsequent disease progression.
difference in prostate cancer mortality, though there
was some improvement in mortality from any cause (the One way to overcome the complex effects of multiple,
reasons for this are still debated). However, strikingly, diverse, and - within a tumor - heterogeneous mutations
the time course to the onset of disease progression is to treat patients earlier in the course of their disease,
after first line ADT, was identical, irrespective of whether and this was the thinking behind the STAMPEDE trial,
the ADT was given immediately, or delayed [16] . Why which tests a number of additional therapies, given
might the time at which so-called “hormone resistant” alongside first-line ADT. This has already borne fruit,
disease is detectable be independent of when ADT was with chemotherapy using docetaxel being recognised
given? Almost the only explanation, if the findings are as the new standard of care, in combination with ADT,
generalisable, is that resistant disease has emerged for patients with metastatic disease who have not yet
from a resistant sub-population that was present at had long-term hormone therapy, following reports from
the time of the initial therapy. Is this true? We need our the STAMPEDE and CHAARTED trials that docetaxel
scientists to answer this question. given at this time improved overall survival with a
25% reduction in the odds of death [2,23] . Results from
Of the novel anti-androgens described above, one in the addition of abiraterone to ADT in the STAMPEDE
particular deserves mention. Abiraterone acetate is trial, and also in a second trial called LATTITUDE, are
an inhibitor of androgen synthesis, via dual inhibition expected imminently. Many questions arise from these
of the 17a-hydroxylase/C17,20-lyase enzymes, and it studies: what is the mechanism of the benefit showed
reduces testosterone levels in untreated men [17] . For by docetaxel? Which patients benefit, as surely not all
274 Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ November 17, 2017