[MUSIC]
Good morning. My name is Rahul Aggarwal,
a geo medical oncologist at UCSF.
Thank you everyone for joining.
Over the next few minutes,
I will give a brief overview of
systemic treatment options for patients with
a rising PSA after prior surgery and or radiation.
We'll start with a brief case example
that highlights the scenario we will be discussing.
This was an actual patient of mine,
68 year-old male with Gleason 4 plus
4 prostate cancer diagnosed in 2018.
He underwent surgery followed by radiation.
His PSA was undetectable
but then subsequently started to rise
crossing the 0.2 threshold that
defines biochemical or PSA recurrence.
At a PSA level of 0.8,
he underwent a PSMA PET scan which did
not demonstrate any PET avid lesions.
Therefore he was not
a candidate for metastasis directed therapy.
Not detecting a spot on
the PSMA PET happens about one-third
of the time with a PSA level between 0.5 and one.
At this point, what are
the treatment options for this patient with a rising PSA?
Risk stratification is key.
For those with low risk,
surveillance is a very appropriate option delays
the side effects and toxicities that can be
associated with Androgen Deprivation Therapy.
For high-risk situations,
hormonal therapy is likely to be warranted at some.
Pertinent questions remain such as when to start?
For how long should we treat?
What type of hormone therapy should be given?
The best way to risk stratify between
low and high risk situations
is to use the PSA doubling time.
This is easy to calculate with
readily available online tools.
These are the results from a long-term study of
natural history following patients
with rising PSA after surgery.
The prostate cancer specific survival
is shown along the x-axis,
starting from the time of PSA recurrence,
meaning when the PSA rose above 0.2.
With time, the proportion surviving
drops from a 100 percent across all groups.
However, you can see for those patients with
the slowest PSA doubling time
that's greater than 15 months,
as represented by the top curve.
The vast majority of patients were alive
15 years from recurrence
without any additional treatment.
Those were the shortest PSA doubling time
of less than three months.
The risk of prostate cancer mortality
is much higher in the absence of
treatment for the median survival
of approximately five years.
It's important to emphasize that
this was a natural history study,
meaning that these patients did not
receive treatment for PSA relapse.
It was also a group of men enrolled multiple decades ago.
Survival outcomes, outcomes for patients with
prostate cancer has significantly improved since then
but nevertheless, the separation of the
survival curves shown in the graph on
the previous slide demonstrates utility of
the PSA doubling time to risk
stratify patients into low and high risk groups.
Generally speaking, a PSA doubling time of
nine months is often used as
a cut point to distinguish these groups.
For high-risk patients for the shorter PSA doubling time.
When is the right time to start hormone therapy?
There really is not
a one size fits all approach to this question.
Several studies have demonstrated at
earlier rather than delayed hormone therapy,
particularly before development of
distant metastases on a scan likely benefits patients.
Our general practice here at UCSF is to aim to start
androgen deprivation therapy summer in the range of
a PSA between three to 10 nanograms per milliliter
but this depends on many factors.
We discussed the importance of PSA doubling time and
additional factors include the absolute PSA level,
patient preference including their experience
on prior hormonal therapy,
as well as patients' medical conditions,
including history of cardiovascular disease,
diabetes, and overall estimated life expectancy.
For those patients who start on hormone therapy,
what is the optimal duration of treatment should
we give hormone therapy continuously until resistance?
Or should we do so intermittently?
In which we give androgen deprivation
for a fixed duration of time,
typically in the nine to 12 month range.
Then PSA suppressed, we stop treatment.
Then as a PSA starts to
rise at a pre-specified time-point,
we start treatment again.
We now have very little solid data from
a large randomized phase three study that tells
us that intermittent hormone therapy has
similar long-term survival as continuous therapy.
Yet with fewer side effects,
better quality of life,
and potentially a longer time until hormone resistance.
Shown on the right is
the Kaplan-Meier survival curve
from this phase three study.
As you can see, the two arms are nearly
overlapping when it comes to long-term survival outcomes,
meaning similar outcomes with either approach,
but better quality of life with intermittent therapy.
Generally speaking, for our patients,
we treat here at UCSF.
We give intermittent hormone therapy for
appeared somewhere between nine to 12 months.
Then we stop and we watch and follow
both the PSA and
testosterone during the surveillance case.
Next question that comes is what type of
hormone therapy can be given for
patients with a rising PSA?
The most common type of immunity
is Lupron or equivalent brand.
There are alternatives, however,
including the LHRH antagonists such as degarelix,
or more recently, the newly FDA
approved oral medication Relugolix.
Both Degarelix and Relugolix lower testosterone
more rapidly than Lupron.
However, longer-term disease controls appears to
be similar with all of these different treatments.
One potential difference between Lupron and Degarelix is
highlighted in the phase three study
comparing these two medications,
as shown on the right side of the slide.
In this study, they randomized men to
receive either Degarelix or Lupron and
treated patients for a period of 12 months and then
stopped as part of an intermittent treatment approach.
They then measured the time until
testosterone recovery as shown in the plot on the screen.
As you can see, the time to
testosterone recovery was faster
with Relugolix compared with
Lupron shown on the orange curve
for Relugolix versus the blue curve for Lupron.
For patients for whom we're
planning intermittent hormone therapy,
who wished to have a more rapid testosterone recovery
following treatment break.
This is potentially an option to consider.
There are also techniques to avoid testosterone lowering
therapy altogether and instead
block the testosterone receptor.
We call this peripheral androgen blockade in
often use a medicines such as
beta glutamine, Casodex alone.
For this approach, there
are trade-offs with this approach.
Potentially fewer side effects,
including sexual side effects compared to Lupron,
but a higher rate of breast enlargement
and nipple tenderness and uncertainty whether
intermittent treatment with peripheral blockade
leads a similar disease control
off treatment as we see with Lupron.
One question that often comes
up is whether or not we should add
a second generation hormonal agents such as abiraterone.
Patients with a rising PSA.
Currently there are no strong clinical trial data
to support this approach, although there
are several ongoing phase 3 studies underway.
One exception to this rule is for
the patient who has a rising PSA.
No distant metastases on
conventional imaging such as a CT-scan and bone scan
but who has multiple distant metastases on
a PET scans such as an axial PSM PET.
In this case, there are too many lesions to
consider for metastasis directed radiation.
A reasonable argument can be made to
intensify hormonal therapy with
a combination of Lupron
plus a second generation hormonal agent,
such as abiraterone or enzalutamide or apalutamide.
Our take home points are the following.
PSA doubling time is a very useful and quick way to risk
stratify patients who have
a rising PSA after surgery and or radiation.
Surveillance is completely acceptable for
approach for patients with
those who have a slow doubling time.
This potentially allows the ability to have
a repeat PSM PET scan at a slightly higher PSA level
when the likelihood of detection maybe higher
and may offer the opportunity passes directed therapy.
For patients who are at higher risk disease
who need to start hormone therapy.
The data support intermittent rather than
continuous hormonal therapy as the standard of care.
A decision on when to start depends on many factors.
Generally, I don't recommend treatment intensification
with combination hormonal therapy for
rising PSA patients only
except those with multiple regions
attempted on PET imaging.
With that, I will wrap up,
thank you very much for your attention.
[MUSIC]