In the late 1980s and early 1990s it was generally considered that men diagnosed with metastatic (but still hormone sensitive) prostate cancer had an estimated survival of 18 to 36 months from the time of diagnosis — including their time on treatment with hormonal therapy. And prior to 2003, there was no known treatment that had any meaningful effect on the survival of men who had a rising PSA after they had started on hormonal therapy.
Many specialists in the treatment of advanced prostate cancer (and at least some of their patients) are convinced that the overall survival of men with metastatic prostate cancer is much longer today than it was in the early 1990s. We have been told that the median survival of a man diagnosed with metastatic prostate cancer today may be as much as 5-6 years, but actual data to support this belief are very hard to come by.
It does need to be recognized in this discussion that most men today are not being initially diagnosed with extensive, metastatic prostate cancer that is widespread in the boney tissues. Rather, the majority of men with metastatic disease today are men who have progressed through various stages (including micrometastatic stages) until their doctor can say, “Yes, there is a clear signal of metastasis on your bone scan.” In other words, they are commonly being diagnosed with an early form of metastatic disease because we have “stage-shifted” the development of prostate cancer as a consequence of earlier diagnosis and earlier treatment.
There have now been several publications from clinical studies providing information on the survival of patients who have ceased to respond to standard, traditional forms of hormone therapy (e.g., an LHRH agonist alone, orchiectomy alone, or some forms of hormonal combination). In recent years, the earlier terms “hormone refractory prostate cancer” (HRPC) and “androgen independent prostate cancer’ (AIPC) have, in fact been replaced by the term “castration-resistant prostate cancer” (CRPC). A significant subset of these men are defined as having metastatic CRPC (mCRPC), meaning that they have evident metastasis on a bone scan or a CT scan, and that they have failed at least two forms of hormonal therapy (customarily an LHRH agonist and an antiandrogen and withdrawal of the antiandrogen).
The first drug combination to show any impact on the treatment of men with mCRPC was docetaxel + predisone. In the so-called TAX 327 study, according to long-term survival data published by Berthold et al. in 2008:
- For men receiving docetaxel + prednisone every 3 weeks, the median survival was 19.2 months, with a range from 17.5 to 21.3 months.
- For men receiving docetaxel + prednisone once every week, the median survival was 17.8 months, with a range from 16.2 to 19.2 months.
- For men treated with mitoxantrone + prednisone, the median survival was 16.3 months, with a range from 14.3 to 17.3 months.
(Remember that the combination of mitoxantrone + prednisone had shown no impact on patients survival in earlier trials; its only effects were on pain and quality of life.)
In April 2009, the results of the IMPACT trial in men with minimally symptomatic mCRPC were announced. According to the product prescribing information for sipuleucel-T (Provenge):
- For men receiving three doses of sipuleucel-T, the median survival was 25.8 months, with a range of 22.8 to 27.7 months.
- For men receiving three doses of a placebo (a “dummy” injection), the median survival was 21.7 months, with a range of 17.7 to 23.8 months.
It is important to note that these patients had generally less advanced disease than the men in the TAX 327 trial, which is reflected in the fact that the men in the placebo arm of the IMPACT trial had a median survival 5.4 months longer than the men in the mitoxantrone + prednisone arm of the TAX 327 study. On the other hand, the patients enrolled in the IMPACT study could already have been treated with docetaxel.
At the Genitourinary Oncology meeting in San Francisco, earlier this year, data were presented showing that cabazitaxel (Jevtana) + prednisone was able to extend (by 2.4 months) the survival of men with mCRPC who had a rising PSA after treatment with docetaxel + prednisone compared to a placebo (a sugar pill) + prednisone. According to the cabazitaxel prescribing information:
- For men receiving cabazitaxel + prednisone, the median survival was 15.1 months, with a range of 14.1 to 16.3 months.
- For men receiving a placebo + prednisone, the median survival was 12.7 months, with a range of 11.6 to 13.7 months.
So we know that docetaxel + prednisone given every 3 weeks can extend median patient survival by 2.9 months compared to mitoxantrone + prednisone, and we know that cabazitaxel + prednisone can extend median patient survival by another 2.4 months for patients who have a rising PSA after treatment with docetaxel + prednisone, giving us a total theoretical median survival benefit of 5.3 months or a median survival of about 21.6 months after initiation of treatment with docetaxel.
Interestingly, a small (non-randomized) study just published by Shamash et al. suggests that a regimen as simple as diethylstilbestrol (DES) + dexamethasone has a significant impact on the survival of men with CRPC:
- For men treated with DES + dexamethasone, median overall survival was 18.3 months, with a range of 15.4 to 23.3 months.
However, there are other things that we really do not know:
- We don’t really know whether hormone therapy still provides only 3 years of survival from the time of first diagnosis of metastatic disease — because most men today start to receive hormone therapy long before there are clear signs of metastasis (and there are at least some data — e.g., the Messing et al. data from ECOG 3886 – that suggest that early use of hormonal therapy may be able to significantly extend survival).
- We don’t really know whether the use of various types of intermittent hormonal therapy might affect overall survival in men with metastatic disease; some would certainly argue that the use of 5α-reductase inhibitors (5-ARIs) as “bridging” therapy in between sessions of standard hormone therapy impacts disease progression and potentially impacts survival — but we don’t have “proof” in the form of data from a well-conducted, randomized clinical trial.
- We have no idea whatsoever of the potential overall survival of men with minimally symptomatic mCRPC who are treated sequentially with sipuleucel-T, then docetaxel, then cabazitaxel. Is their median overall survival > 25.8 months?
- We don’t even know the optimal timing of chemotherapy with docetaxel + prednisone in a man with a rising PSA after treatment with sipuleucel-T. Does that have to be based on some other signal of disease progression? We do know that treatment with sipuleucel-T has no significant impact on time to disease progression (as opposed to overall survival).
And all of this comes while we are investigating the clinical effects of a host of new products (abiraterone acetate, ipilimumab, dasatinib, MDV 3100, etc.) that might get used before, after, or in conjunction with the treatments that are already available.
From the viewpoint of drug developers, the overall survival of patients with late stage prostate cancer is not of the highest priority. Their highest priorities are: (a) demonstrating that their [new] drug does something better than the current standard and (b) optimizing belief that their product(s) represent some new and better standard. The most recent example of this is seen with cabazitaxel. The primary goal of the developer was to show that cabazitaxel therapy could extend the survival of patients with mCRPC when the patients were no longer responding to docetaxel (the standard of care of first-line treatment of mCRPC) so that it became the new “standard” for the treatment of patients who ceased responding to docetaxel-based chemotherapy.
From the viewpoint of a patient, however (and we hope from the viewpoint of his doctor too), the key question is shortly going to become, “What is the sequence of treatments that will optimize the survival of a patient with a rising PSA after first- and second-line treatments and who can be assumed to have micrometastatic prostate cancer?” Such men can already live for 15+ years with their cancer, but that isn’t true for all men with micrometastatic disease. There are others who are at risk for a much earlier demise because they have especially aggressive, andogen-resistant forms of prostate cancer.
The prostate cancer community needs to come together to work out how best to answer the above question — and it isn’t going to be easily or quickly resolved.