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Previously, we have discussed the conundrum of the rising PSA and when to start therapy. I also opined that for some men with a very slowly rising PSA, it might be best to just forget about it and enjoy life, comparing it to watching a clock, an opinion that understandably garnered negative comments from some. Of course the nuances surrounding PSA kinetics and their meaning are myriad. However, one graphic that helps understand this better is shown here.
Smith, JCO 2013
This figure illustrates the fact that individuals with relatively long doubling times (>8-10 months) have a much lower risk of developing metastases or dying from prostate cancer than those with shorter doubling times. In a classic study published almost 2 decades ago, Pound et. al. followed a large number of patients who had rising PSAs following prostatectomy at Johns Hopkins. On average, men with rising PSA’s who received no additional treatment, did not develop metastases for ~8 years. “In survival analysis, time to biochemical progression (P<.001), [i.e. the time from prostatectomy until PSA rise was detected] Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease.”
With these findings as a background, two studies were presented at the ASCO GU18 meeting, both involving use of improved analogues of bicalutamide (Casodex): enzalutamide (Xtandi) or apalutamide (Erleada). These drugs block the androgen receptor, thus preventing stimulation of prostate cancer growth, but are more potent than bicalutamide. Patients with rising PSA’s in spite of having low levels of testosterone from surgical (orchiectomy) or medical (GnRH agonists/antatgonists) castration, short doubling times (<10 months), but no metastases were treated either with apalutamide/placebo (SPARTAN trial) or enzalutamide/placebo (PROSPER trial). The trials were both remarkably positive in delaying the time to development of metastatic disease.
SPARTAN TRIAL (Apalutamide)
PROSPER TRIAL (Enzalutamide)
These are remarkable findings and great news for patients with the most aggressive forms of prostate cancer. However, there are (as usual) numerous questions raised by the trials, as was nicely discussed by Dr. Kantoff after the data were presented. These included a more careful analysis of the side effects and clinical benefits. Obviously patients are psychologically better off when they don’t have a rising PSA or metastases, but neither study reached statistical significance when it came to improved survival (both are trending in this direction). What are the side effects of being on such drugs for longer periods of time? In the enzalutamide study, there were more deaths from “other causes” – not pca within 3 months of progression. Why? In the apalutamide study there were more falls and fractures compared to placebo. Why? To these, I would add the issue of “pay me now or pay me later” – how much time/quality of life do you really lose by waiting until the first metastasis shows up, never mind the extraordinary costs (to patients, insurers, medicare, etc.) of remaining on these drugs for years. Further, neither study compared the outcome to using bicalutamide, the generic and much cheaper alternative anti-androgen, instead of placebo. And what about using the newer scans? All of the patients have metastatic disease, we just can’t see it until there are enough cells in one spot to turn a scan (e.g. fluciclovine or PSMA PET) positive. We can possibly gain advantages in staying off ADT of any sort in some patients by radiating oligometastatic disease. Nevertheless, these studies are great progress and landmarks in the fight against prostate cancer. Apalutamide became the first drug to be approved by the FDA for use in this setting with a “snap approval“. And I need to disclose that I am a paid advisor to J&J, although I have no personal stock in their company, and did not treat patients on either trial.
prost8blog 
Thank You Dr. Glode. Do you see a possible use for this drug in metastatic patients who have failed xtandi or zytiga? Or will those patients have to wait for darolutamide. Thank You
Dan
Founding member New Denver Mens Club
Not sure. Since the AR is the same target for all of the “lutamides” I suspect there will be a fair amount of cross resistance. Patients who progress on zytiga do not have as high a response rate to xtandi. There is probably only so much you can accomplish by attacking testosterone/AR.
The first graph — PSADT vs “relative risk” — is somewhat deceiving.
The “relative risk” range shown is from 1.4 to 3.0. If you re-draw that graph _with the RR scale starting at 0_, a different message comes out:
. . . Don’t think that a long PSADT means that you won’t get metastatic disease.
You are _less likely_ to metastasize, but your risk is way greater than 0.
The trial results — those are really nice! Thank you —
. Charles
I don’t disagree (much). However, the graph is far more encouraging than a straight line would be. Further, in our study of 2 years of hormone therapy +/- 6 cycles of mitoxantrone immediately after prostatectomy in men with adverse pathology, the majority of men died of other causes, not pca. I think it makes sense to focus our efforts (and undesirable toxicities) on the guys with high Gleason scores and/or short doubling times, just as we have backed off aggressive treatment of newly diagnosed Gleason 3+3 patients, many of whom are now watched.
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