
Prostate cancer drug so effective trial stopped - joeyespo
http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2012/06/02/MNI11ORI84.DTL
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tshtf
Apparently this drug[1] was discovered at non-profit Cancer Research UK[2],
not a drug company.

1\. <https://en.wikipedia.org/wiki/Abiraterone>

2\. <https://en.wikipedia.org/wiki/Cancer_Research_UK>

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mrkmcknz
Johnson & Johnson own the rights to this drug they purchased it sometime ago I
believe.

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ars
Yah, it was discovered in 1990, and goes off patent in 2 years.

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pixelcort
This has interesting implications to the recent discussions about A/B testing
and Multi-armed bandit algorithms.

Assuming double blind tests are akin to A/B testing, at what point was the
trial stopped? Was it stopped before there was statistical significance?

Or, are there differences in how double blind tests are done than how A/B
testing is done in software and websites?

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Gatsky
I was at the announcement of the trial data by the investigators this morning.
The results were also discussed by a statistician not involved with the trial
directly. Not sure that hacker news needs an in depth analysis of the trial
design and outcome, but anyway...

In summary, the trial looked at patients who had incurable prostate cancer
that had spread and stopped responding to traditional hormonal treatments.
Patients had to have no symptoms to be enrolled on this trial. The trial
compared abiraterone, a new type of hormonal treatment plus steroids to just
being on steroids alone. The question that the trial was asking can be framed
as "Does taking abiraterone prolong the period of time that a patient can be
symptom free and their cancer is under control?" That was the primary
endpoint. A secondary endpoint was survival, or how long they lived.

Built in to the study design was a planned interim analysis of the data.
Normally, the investigators are not allowed to just look at the data as it
accrues continuously because it creates bias. It is a standard approach to
allow one look at the data when say 40% of the expected events (in this case,
development of progressive cancer) have occurred. When they did this, the
difference between getting the drug and not getting the drug was considered
big enough to unblind the trial. This means that everyone finds out if they
were getting placebo or the real drug.

There are multiple reasons why one may decide to do this. First and foremost
is that if the drug really works, it would be unethical to leave people on a
placebo for long periods, because it is clear they have an inferior outcome.
Stopping early also speeds the time to drug approval and market entry for a
given indication.

There are somewhat esoteric statistical procedures that can determine at an
interim analysis if the accrued data shows a statistically significant
difference between groups, which would therefore justify stopping the trial,
while adjusting for the impact of repeated testing on the type I error rate
(ie the chance of finding an association that doesn't really exist). In this
trial, there is no doubt that the primary endpoint was positive and clinically
and statistically significant, even with only 40% of people on the trial
having had a progression event. So they stopped. The data on whether
abiraterone reduces the chance of death are not mature, because not enough of
the people on the trial have died yet, so those results will be awaited.
Stopping early means that these results may be biased however, because the
trial is no longer blinded.

This was a large and well done trial, that employed standard statistical
practices.

~~~
firebones
Does the placebo group get the option of getting the med at the time of
termination, or do they have to wait for approval along with everyone else?
What about the group already getting the med? Do they stay in?

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Gatsky
The drug company always continues to provide the drug to those people already
getting it, at least in every trial I've ever seen.

The placebo group... it depends on the trial. There are some trials where
crossover to the active treatment is not permitted, and patients may die
without getting it. The problem is that if you allow crossover, usually that
means that the trial will not show a difference in overall survival,
paradoxically because the treatment works really well. Regulatory bodies such
as the FDA demand positive survival data in some cancers before they will
approve a treatment. So it can be a difficult ethical issue, because although
it sounds terrible to deprive the placebo group of treatment, if you don't
prove it works then it won't get approved and nobody will get it outside of
the trial.

The investigators didn't say whether they allowed crossover in this trial. It
probably doesn't matter too much, because abiraterone is already approved and
available at the moment for use after patients have had chemotherapy with
docetaxel. So for example, patients that progressed on this trial could go on
to receive docetaxel which might control their disease for a while, and then
after that they could access abiraterone, so they wouldn't necessarily miss
out. Is it better to have abiraterone and then docetaxel, or to have docetaxel
and then abiraterone? That's an open question, which may never get tested in a
clinical trial. Generally the order doesn't matter as much as being exposed to
all the agents that are active. In an elderly patient who is a bit frail, I
think most patients and doctors would prefer to use abiraterone up front
rather than chemo, which has more side effects.

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losvedir
Ah, yes, abiraterone. In another life, when I did equity research, we covered
Cougar Biotech (the owners of the drug before JNJ). Even then (years ago), it
was clear this would be a successful drug. Glad to hear science and drug
development are moving forward!

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lonnyk
Please elaborate on what made it clear so long ago.

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losvedir
It did very well in all its trials. To get approved for use in any indication
a drug has to go through a number of clinical trials - a Phase 2 in a small
group of patients and multiple Phase 3's in a larger group.

And that's for one indication only. So a cancer drug might try to get approved
for "4th line" use in some cancer, meaning the FDA says it's okay to use after
3 other drugs have failed. After some success there, the drug company might
push to expand its label into 3rd line or front line treatment and sponsor
more clinical trials to compare it to the drugs currently used at those times.

I don't know what trial this article was talking about specifically, but there
were a number of other trials abiraterone did spectacularly in beforehand.
Unfortunately, I don't recall the specific data from years ago when I kept up
with this stuff.

Cancer drugs frequently "work", but just barely, stopping the progression of
symptoms for a few months or so, and this is enough to get approved. On the
other hand, you have Gleevec[1], which turned a certain variety of leukemia
from invariably fatal to a death rate of just 1%. Its efficacy was noted early
in the trials and got approved quickly.

Similarly, abiraterone's efficacy showed clearly in the early trials, although
it's somewhere in the middle of the spectrum between "barely efficacious" and
Gleevec.

[1] <https://en.wikipedia.org/wiki/Imatinib>

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domwood
As someone who's grandfather and grandmother both died of cancer-related
complications (edit: in the last four months, my grandmother not even a week
ago) and with a grandfather-in-law who has terminal cancer, for once I'm going
to abandon cynicism, gloss over the lack of scientific details, and dare to
hope.

~~~
tsotha
Don't go overboard. This drug works by suppressing the ability of cancer cells
to produce testosterone, which prostate cancer cells need to grow. So it isn't
effective against any other type of cancer.

Also, I would bet my last dollar the cancer will eventually find a way around
it since cancer cells mutate like crazy. So it's probably a question of adding
some time to the patient's life instead of curing or even controlling the
disease. And there are side effects.

Don't get me wrong - if I have terminal prostate cancer I'm gonna pop these
pills like candy. But it's only going to help men with aggressive prostate
cancer that can't be cured with surgery because it's already metastasized.

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domwood
No, it's no wonder drug, it's not a cure, it's a treatment. Yes, it probably
will become redundant eventually, but as cancer's a genetic thing, it'll be on
a patient by patient basis, that means even if a patient's cancer start to
develop an immunity to the drug, it'll take a very long time for that immunity
to be spread by reproduction, especially as people _tend_ to get cancer after
having children (it's far more common in later life after all, or don't have
them after they are diagnosed. That means that it'll be useful for a long
period of time for the majority of people. In the meantime, that gives science
a chance to continue to develop the "next step", whatever that may be. And
it's not the only drug of its kind, we've got to the point of being able to
target individual cancers, so perhaps the research from this will have uses
elsewhere.

P.S. I'm not going overboard, cancer has done a damned good job of rampaging
through my family, so I think I'm excused a little drama ;)

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tsotha
>Yes, it probably will become redundant eventually, but as cancer's a genetic
thing, it'll be on a patient by patient basis, that means even if a patient's
cancer start to develop an immunity to the drug, it'll take a very long time
for that immunity to be spread by reproduction...

Eh? I guess "never" is a very long time. Prostate cancer isn't communicable,
and while you may pass a propensity to get cancer to your offspring that's
irrelevant to the treatment.

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geuis
Story is a bit light on details. Can anyone provide links to the study and the
rationale behind ending it early?

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notatoad
according to the commenters on reddit, the rationale behind ending it early is
that _this is how clinical trials work_. A trial is run until it is
statistically clear that a drug is either better or worse than the current
market leader it is being compared against. The trial might be ending earlier
than expected, but it is not being cut short. The success metrics were
reached.

~~~
refurb
Clinical trials are monitors by IRBs (institutional review boards) that
independently monitor the trial to ensure that it is being conducted
ethically.

It's not odd at all for a trial to be ended early if the drug being tested is
obviously better than the control arm. It's especially true in trials that are
testing drugs for potentially lethal diseases like prostate cancer.

What likely happened was that an interim data review was conducted, the
results showed that the new drug was substantially better than the control arm
(and statistically significant) and the IRB and sponsoring company decided
that it had an ethical obligation to end the trial and provide the drug to all
the patients.

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novalis
This brings great hope to all affected and I hope it gets approved and helps
the people that have not gone through chemo yet, as stated in the article.

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RexRollman
Let's hope that this drug works as well for everyone as described in the
article.

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mathattack
Great news!

For better or worse, there's a lot of benefit from rich people dedicating
their lives to beating drugs like this. In a perverse way, Mike Milliken
getting prostate cancer was one of the best things for beating this cancer.

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ck2
Now let's hope people in the USA without insurance can afford it.

It certainly will be a lucrative, profit-making drug and the temptation will
be high to milk it for all it's worth.

~~~
refurb
Two comments:

1\. Practically no one in the US who needs expensive chemotherapy drugs goes
without them. Either the patient goes to a 340b hospital and the hospital
treats for a lower or zero cost or the patient qualified for programs that the
manufacturer runs where the drug is provided for free.

2\. Compare the situation in the US to the UK where the gov't said
"abiraterone" is not worth the price and patients couldn't get it at all,
unless the paid out of the pocket for it.(1) Do you think that's a better
situation than the US?

(1) The UK gov't body NICE just decided in May to approve the use of
abiraterone because the company decided to offer a discount. The current cost
is a little under 3000GBP/month.

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arethuza
It's not a choice in the UK between the NHS or pay or it yourself - you can
have private health insurance if you want.

