There has been regular discussion here and elsewhere about the degree to which new forms of therapy have impacted patient survival since the original approval of docetaxel for treatment of metastatic, castration-resistant prostate cancer (mCRPC). The one thing that has always been clear (at least to your sitemaster) is that one couldn’t just “add up” the median survival benefits of all the new drugs and assume that the total would be the degree of absolute benefit.
We had not noticed this at the time, but — as of February 2018 — we have had some much more concrete information about this topic from one of the very best cancer centers in the world: the Dana-Farber Cancer Institute (DFCI) in Boston.
At the Genitourinary Cancers Symposium in San Francisco, earlier this year, Francini et al. reported data from a total of 583 patients, all diagnosed with (or progressing to have) and treated for mCRPC at DFCI and whose data were compiled in the DFCI Clinical Research Information System.
Francini et al. subdivided these patients into two cohorts, as follows:
- Cohort A included men diagnosed between 2004 and 2007, when their initial treatment options for mCRPC were limited to docetaxel, mitoxantrone, first-generation anti-androgens, estrogens, steroids, and ketoconazole, with only docetaxel known to have an overall survival benefit.
- Cohort B included men diagnosed between 2010 and 2013, during which period, or relatively soon thereafter, five important new agents became available for the treatment of mCRPC: sipuleucel-T (Provenge), cabazitaxel (Jevtana), abiraterone acetate (Zytiga), enzalutamide (Xtandi), and radium-223 (Xofigo).
Here are the core study findings:
- Average (median) follow-up was
- 10.6 years for patients in Cohort A (n = 317)
- 4.6 years for patients in Cohort B (n = 266)
- On multivariate analysis, the number of different types of therapy administered to the patients was
- ≤ 3 for the men in Cohort A
- 5 to 12 for the men in Cohort B
- Average (median) overall survival was
- 2.2 years for patients in Cohort A (range, 2.0 to 2.4 years)
- 2.8 years for patients in Cohort B (range, 2.5 to 3.2 years)
- 5-year overall survival was
- 10 percent for the patients in Cohort A
- 26 percent for the patients in Cohort B
- There was a 31 percent decrease in risk of death from any cause at 5 years among patients in Cohort B compared to Cohort A.
- There was a more substantial effect on long-term survivors, with a 2.6-fold increase in 5-year overall survival.
What this means is that even ay an institution like DFCI, where one could reasonably expect any patient with mCRPC to have been receiving a very high standard of care between about 2004 and 2017, the access to the latest types of approved treatment (and probably one or two other investigational agents as well) since 2010 has only shown
a modest impact on [overall survival], with a median improvement of 6 months.
Thus, for the majority of patients, mCRPC is still a condition with a distinctly limited survival opportunity and these new agents seem to have provided a limited degree of additional benefit, but …
As one might also have expected, there is a subset of long-term survivors (i.e., the patients surviving for an average of 5 years or more) that do seem to have benefited to a greater extent from access to these new agents. And the new agents do seem to have enlarged the size of this subset of men considerably.
We would just note, for emphasis, that if one adds up the individual, median overall survival benefits of the five new agents used in and initially approved for the treatment of mCRPC since 2010, i.e., sipuleucel-T (4.1 months), cabazitaxel (2.4 months), abiraterone acetate (4.4 months), enzalutamide (4.8 months), and radium-223 (2.8 months), the total comes to 18.5 months, which is more than three times the median benefit actually observed by the group at the Dana-Farber.
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: benefit, castration-resistant, Dana-Farber, metastatic, overall, survival |
THE "NEW" PROSTATE CANCER INFOLINK 
Much to comment on here … but for starters an observation/interpretation that would lead me to conclude we have made very significant headway.
The median overall survival in the Dark Ages of Cohort A was only 26.4 months; Cohort B is 33.6 months or 27% more … that is good by any standard.
The fact that the original (A) level was as low as 26.4 months deserves comment. Most genitourinary med/oncs, when pushed, will give a pretty much pat standard answer to men who have recently become metastatic that their life expectancy is around 60 months. So these numbers seem low — making me wonder how sick the population was at time of diagnosis.
We know that overall survival numbers can be easily distorted. The 4.1 months attributed to Provenge can largely be explained by how advanced the men were when they received the drug. The principal investigator will now tell you, as will the company, that administering the drug with a much lower tumor burden provides better results.
Similarly, from my purely anecdotal experience, since the widespread use of abiraterone acetate and enzalutamide for men with mCRPC, many more have lived longer than 34 months than less.
What concerns me with this research, and is already occurring, is that it discourages men. I am getting calls from men reading this who are dismayed, disillusioned about treatment options, and pessimistic. Much of my job as an advocate is to help men maintain hope, not false but realistic hope. Albeit intangible, when men give up hope they decline quickly.
I do not believe these numbers tell the whole story — but for what reason I cannot say.
Dear Rick:
As you well know, I am a great believer in helping men to have as much hope as possible. However, I also believe that it is important for them to have access to whatever high-quality data is available. So, I would point out to you that:
— Back in 1989, when flutamide was first approved, the time that men were told they had to live if they were initially diagnosed with metastatic hormone-sensitive prostate cancer (then known as stage D2 disease) was 18 to 36 months. The median actuarial survival of the men (stage D2, previously untreated) in the pivotal trial leading to the approval of flutamide was 34.9 months for patients treated with leuprolide + flutamide versus 27.9 months for patients treated with leuprolide + a placebo. Again, these were all newly diagnosed, hormone-sensitive patients.
— In your comment you state that, “Most genitourinary med/oncs, when pushed, will give a pretty much pat standard answer to men who have recently become metastatic that their life expectancy is around 60 months.” That is roughly double the overall survival time for men after they have first been identified as having metastatic disease since 1990, i.e., over the past 28 years.
— If the expected median survival time of men identified as having metastatic castration-resistant prostate cancer is now 33.6 months (up from 26.4 months in the early 2000s), that actually correlates very well with the idea that projected median overall survival from time of onset of metastasis is now around 5 years or 60 months.
You need to bear in mind that (because of their ages and their co-morbidities) an awful lot of men with metastatic prostate cancer die from things other than their prostate cancer, and that there is an important distinction between overall and prostate cancer-specific survival. It is perfectly reasonable to believe that, if a man doesn’t die of anything else first, the median survival of men who have metastatic hormone-sensitive prostate cancer might be significantly greater than 60 months and that the median survival of men with metastatic castration-resistant prostate cancer might be significantly greater than 33.6 months.
Prognosis Against Metastatic Prostate Cancer Back in the Day and Now
Rick and Sitemaster,
I’m thinking this Dana Farber study is indicating the lower boundary of the survival benefits of the new drugs and supportive technology. I am confident these figures, which already are worthy, will be improving a lot within the next few years. My viewpoint is influenced by what has happened in the past.
Your discussion of prognosis really brings back memories for me. Back in late 1999/early 2000, my case was in the questionable zone for metastasis: considered likely because of a PSA over 100 and a “rock hard” prostate, but with technetium bone and CT scans negative, and only one unlikely area deemed “suspicious” based on a ProstaScint scan in early 2000. I was well aware of the short prognosis estimates for men with metastases, having had two knowledgeable urologists at the City of Hope and Johns Hopkins give me a prognosis of 5 years — amounting to 60 months of course. But I was also aware of more encouraging viewpoints. I got a huge morale boost when I first learned of the paper by Oefelein, Agarwal and Resnick (Cleveland Area, Case Western Reserve University) back in 2004, my fifth year on then intermittent ADT3 for my life-threatening case. Here are key lines of your discussion on this point, quoting from Sitemaster’s response:
“… In your comment you state that, “Most genitourinary med/oncs, when pushed, will give a pretty much pat standard answer to men who have recently become metastatic that their life expectancy is around 60 months.” That is roughly double the overall survival time for men after they have first been identified as having metastatic disease since 1990, i.e., over the past 28 years.
“— If the expected median survival time of men identified as having metastatic castration-resistant prostate cancer is now 33.6 months (up from 26.4 months in the early 2000s), that actually correlates very well with the idea that projected median overall survival from time of onset of metastasis is now around 5 years or 60 months.”
The Oefelein and team study,va retrospective look at their institutional data prompted by the team’s unease with the very short typical prognosis of around 12 to 18 months for men with hormone-refractory prostate cancer, found that “Median survival after hormone refractory prostate cancer developed in patients initially staged with and without skeletal metastasis was 40 and 68 months, respectively.” They counted from the date of the initial elevation of PSA until death, rather than from the date of enrollment or randomization in a clinical trial.
As I was already in my fifth year as a survivor in 2004 and still responding very well to ADT3, with a nadir of < 0.01 (down from the initial 113.6 and flare/pre-Lupron increase to 125), with no physical indication of metastasis, I realized I likely had at least a fair number of years ahead of me. It has now been 19 years and a week since my formal diagnosis, and I think I have been cured (radiation plus supportive ADT in 2013/2014). The latter point indicates the key role of advancing technology, which almost certainly is again playing a key role for men with metastatic, castration-resistant cases who will be getting the new drugs discussed in this paper .
It is also worth underlining that we used to be talking about 12 to 18 months once castration resistance (then called “hormone-refractory” disease) had been confirmed, even without metastasis, where we are now talking about that 33.6 months mentioned by Sitemaster from metastasis, which of course normally comes substantially later than castration resistance. Taking this longer view, that’s a lot of progress!
Dear Jim:
Can you please tell me where you are finding data suggesting that most men are castrate resistant today before they show signs of metastasis? I am not aware of any data that actually demonstrate that fact, and in all truth I think that might only be the case in a small number of Western nations.
Also, your analysis takes no account of the key point that I made about men dying of things other than prostate cancer.
As you point out, if you have data that allow you to track a man’s survival time from initial onset of a rising PSA while on ADT until death, you are going to get a very different number than the one extracted from the Dana Farber data, which is based on “all comers” — even those who initially came to Dana Farber with a PSA in the thousands and extensive metastasis who had never previously been diagnosed or received any form of treatment.
The Dana Farber data are much more closely aligned to the “real world” of prostate cancer treatment than the Oeflein et al. data. You seem to be ignoring the fact that, every year. there are thousands of men (maybe even tens of thousands) who still get initially diagnosed with metastatic disease and PSA levels of 100 ng/ml and higher — in America, in Canada, and in most of the rest of the world too. For those men, when treated according to the protocols used in the CHAARTED, STAMPEDE, and GETUG trials, median overall survival at 5 years is still unknown since most of these trials have only reported the differences in outcome at 3 years or thereabouts (which were clinically and statistically significant).
I find this information very informative as I have advanced prostate cancer (pT3N0); had PSA 10, Gleason 9 in all 12 cores.
Had 45 days of radiation and am currently on 9 months of firamagon
My question to you is: when will the cancer become castration resistant and what are we doing to be ahead of the curve before it starts to change? Is there any test that we are doing out there besides just watching the PSA numbers. Please let me know.
Dear Henry:
It is almost impossible to predict when an individual patient will stop responding to first-line androgen deprivation therapy — i.e., with a drug like degarelix (Firmagon) — when combined with radiation therapy. However, there are ways to know whether early onset of castration resistant prostate cancer (CRPC) is more or less likely, for example:
— If your PSA level doesn’t drop to a nearly undetectable level (i.e., 0.1 ng/ml or less) after treatment with radiation + degarelix, then early onset of CRPC tends to be much more likely.
— If your cancer has certain somatic (tumor specific) genes, then the risk for progression tends to be greater … so you might want to talk to your doctors about having genetic tests run on the tumor samples from your biopsy.
You also need to understand that there are now several forms of “new” drugs that can be added to drugs like degarelix, although this is usually done only after the patient is shown to have CRPC or evidence of metastasis or both. You could talk to your doctors about how early it might be wise to think about adding a drug like enzalutamide (Xtandi), or apalutamide (Eleada), or darolutamide (Nubequa), or even abiraterone acetate (Zytiga) + prednisone to the degarelix. We are not necessarily recommending this … just pointing out that it may be a reasonable possibility for someone like you.
Henry:
I don’t think there is any point in getting “ahead of the curve.” With prostate cancer, I think the best strategy is dealing with what is on your plate at the present moment. First of all, from your description, you do not have “advanced prostate cancer,” you have “high-risk prostate cancer,” which is a very different entity. The difference is important, because there is every reason to believe you are having curative therapy. Going over in your mind all the things that could go wrong needlessly increases anxiety and suffering.
Thank you for getting back to me.
I have the TMPSS2 gene mutated.
Is there another test besides looking at the PSA numbers that we can do to see if the cancer is starting to change before the PSA rises?
It is known that when the BRCA1 gene is mutated then the timeline for the cancer to change seems to be faster on becoming CRPC. What information is on other mutated genes and are there studies out there?
Thank you again for all your assistance in this matter as I am trying to do as much research on this matter as I am dealing with a lot of people in different stages who need some comforting information that some of the doctors and not letting them know except that you got prostate cancer and do this and this and let see what happens.
So any information is very helpful.
Thank you
Henry Cuesta
I am AJCC stage IV with PSA 14.8 ng/ml in 12/2021 (PSA 11.9 in 11/2021) and was diagnosed 12/1998. Any info on prognosis?
Dear Richard:
Your prognosis depends on how you have been treated to date, and you have provided no information about that. If your PSA has just started to rise after several years on androgen deprivation therapy (ADT) — for example — you could still respond well to several other forms of treatment.
Strongly recommend you attend AnCan’s peer-led weekly advanced prostate cancer virtual support group. We hae an amzing brain’s trust of experienc including secereal medical professsionals lving with advanced PCa.
We speak about latest treatmentws and often have men going through them in trials.
Visit https://ancan.org/prostate-cancer/ ; sign up for a Reminder at https://ancan.org/contact-us/. Listen to earlier recorded groups at https://ancan.org/category/recorded-groups/ .