Keywords: prostate cancer, chemotherapy, Docetaxel, androgen, standard of care
How to cite: Petrylak, Daniel. “Early Chemotherapy for Metastatic Prostate Cancer” Grand Rounds in Urology. January 22, 2016. Sep 2019. https://grandroundsinurology.com/prostate-cancer-daniel-petrylak-early-chemotherapy-for -metastatic-prostate-cancer/.
Early Chemotherapy for Metastatic Prostate Cancer – Edited Transcript
The usage of docetaxel for castration resistant prostate cancer was first discussed at the 14th International Prostate Cancer Update twelve years ago. At that time, docetaxel showed a modest survival benefit of about two or three months when administered to patients with metastatic disease. This evidence led to some ambivalence among clinicians about using chemotherapy as a treatment for these patients. Historically, docetaxel has been reserved for castrate resistant patients who are symptomatic and have rapidly progressive disease or a visceral disease. In this presentation, Dr. Petrylak revisits this discussion and presents more recent data, encouraging physicians to consider using docetaxel to treat patients who have high risk metastatic hormone-sensitive disease.
Firstly, Dr. Petrylak describes the process and outcomes of the CHAARTED trial, which was run by Chris Sweeney and published in the New England Journal of Medicine. The hypothesis of this study was that six cycles of docetaxel followed by androgen blockade would lead to superior survival benefits in patients in the early stages of metastatic disease than administering androgen blockade alone. These patients were stratified based upon several factors, including the extent of their metastases, an ECOG performance score of 0, 1, or 2; whether they had received bisphosphonates, and whether they had received prior adjuvant and new adjuvant hormone blockade. Patients who had received prior adjuvant hormone blockade were eligible if the duration of their therapy had lasted 24 months or less and progression had occurred more than 12 months after completion of therapy. Patients were also stratified based on the duration of their prior adjuvant androgen-deprivation therapy (ADT), specifically whether they had received it for less than 12 months or more than 12 months. Patients already receiving ADT prior to the study were permitted to continue only up to 120 days before randomization, and no intermittent ADT dosing was allowed.
Ultimately, 790 men were randomized between July 2006 and November 2012. Arm A of this study received docetaxel, with patients being observed for six cycles until progression and undergoing evaluation every three weeks. No prednisone was given. Arm B of the study received androgen deprivation therapy but did not receive docetaxel, and were also treated until progression. The trial was ended early due to the DSNB’s findings that there was a significant difference in death rate, in favor of the experimental arm.
When reviewing the different groups of patients, in those who had extensive high volume disease such as liver metastases or more than four lesions on a bone scan, there was a significant difference in favor of early-administered docetaxel. Patients being treated with ADT alone reached a median overall survival rate of 32.3 months, whereas those treated with both ADT and docetaxel reached a rate 49.2 months, showing an improvement of 17 months with a hazard ratio of 0.6. For patients with low volume disease, the data for hazard ratios was very similar, at 0.63. In contrast to their counterparts with high-volume disease, however, the data for these patients did not show a significant difference in median overall survival rates for either the ADT-only arm or the ADT + docetaxel combination arm. This indicates the need for further research concerning the effects of docetaxel on patients with low-volume disease.
When viewing secondary endpoints, the trends for both groups follow a similar pattern. For the ADT-only arm, the median prostate-specific antigen level was measured at less than 0.2 at six months. This is a known prognostic factor for patients on hormone therapy. The PSA levels were superior in patients who were a part of the combination arm. In regards to the median time to castration resistance, the data shows an approximate six-month improvement, also in favor of early-administered docetaxel. Perhaps most importantly, the median time to clinical progression as defined by symptoms of radiographic disease showed an approximate 13 months improvement.
It is important to prove that these improvements are due to the introduction of docetaxel and not from other factors, such as one group undergoing a substandard quality of care compared to the other. Evidence that both groups received equal standard of care can be seen in the myriad of surveys taken concerning the group of patients that received chemotherapy, cabazitaxel or docetaxel. This group consists of about 150 patients, which is almost half of the patients studied during this particular trial. Patients also received abiraterone/enzalutamide equally in both arms, so by clinical standards they were also treated by standard of care. According to Dr. Petrylak, the ideal way the trial should have been conducted would have been docetaxel plus hormones and then docetaxel at first progression, but that was not feasible at that particular time.
The data presented by this specific study exhibits that six cycles of docetaxel in addition to androgen blockade represents an appropriate option for those with metastatic prostate cancer who have previously started androgen blockade treatment. Dr. Petrylak recommends that doctors consider discussing this combination as a treatment option for patients who are eligible.
A separate study by the Genitourinary Group (GETUG) group observed the effects of docetaxel on about half the number of patients as were in the CHAARTED study. These patients received nine doses of docetaxel at 80% power, which culminated in a hazard ratio of 0.62. For this smaller research group, the median number of cycles administered was eight, with 48% of patients receiving nine cycles. Physicians observed neutropenia (21%), febrile neutropenia (3%), and febrile neutropenia with infections (1%) in patients of the combination arm in this study.
Similar trends concerning the difference in survival rates between the ADT-only and combination arms, as seen in the CHAARTED trial, occurred with these patients. Improvement in biochemical progression free survival (PFS) reached 23 months versus 13 months for the control arm, and for clinical PFS, there was an approximate eight-month difference. Unfortunately, the overall survival was not statistically significant, reaching 59 months for the combination arm and 54 months for the hormones alone arm.
The theorized reason for this is that there was a higher number of patients with lower volume disease on the GETUG trial, although it is also possible that the problem could be attributed to the timing of the chemotherapy. The overall survival rate does not appear to change when adjusted for further follow-up, indicating that the study is insufficient compared to the CHAARTED trial. A higher rate of deaths unrelated to prostate cancer is also seen, exhibiting a discrepancy in localized disease treatment that may also have enough of an effect to cause the difference in data between the trials.
This theory appears to be confirmed by data from the STAMPEDE trial, a larger study that was performed in Britain. The trial design for this study underwent several adjustments, ultimately resulting in a comparison between patients receiving standard of care, patients receiving standard of care plus zoledronic acid, patients receiving standard of care plus docetaxel, and patients receiving the trifecta of docetaxel and zoledronic acid as well as standard of care. The primary endpoint for this study was overall survival, and the secondary endpoint was PFS or failure free survival. When comparing patients in the docetaxel plus standard of care arm versus those in the standard of care arm, there’s a high number of deaths overall, with 165 deaths occurring in the former and 405 occuring in the latter. This included patients who had locally advanced as well as metastatic disease, which indicates that this study is more extensive than the ECOG study. The addition of zoledronic acid resulted in 181 deaths in the combination arm and 197 deaths in the standard of care arm, showing that zoledronic acid does not contribute as significantly to the overall survival of patients as the addition of docetaxel.
The data regarding patients based upon metastatic disease is where the difference is most significant. There is a trend in failure free survival in those patients who have biochemical relapse or locally advanced disease, although it has not yet matured enough to see a difference in overall survival. For certain side effects in this particular trial, there was little difference made for patients in the zoledronic acid arm. In contrast, there was a higher rate of febrile neutropenia (12%) in the docetaxel and standard of care arm. Because androgen levels affect enzymes, which in turn affect docetaxel metabolism, docetaxel may actually be metabolized differently in these patients. For example, patients may be getting a higher dose intensity that culminates in febrile neutropenia. Consequently, doctors must watch patients being treated for neutropenia more carefully and offer them growth factor supplementation. Another important observation made from this trial is that there does not seem to be much of a difference in the time to the first treatment for failure free survival, as all of the groups report similar rates. Additionally, the time to first life prolonging therapy for progression also does not show a large discrepancy.
Importantly, an update of this data was presented at the January 2016 ASCO conference that articulated the promising possibility of solocoxamid as a treatment for these patients. Data from this update showed that an experimental arm being treated with solocoxamid resulted in a survival benefit very similar to docetaxel. This supports older research that indicates solocoxamid’s capability of down-regulating androgen receptor expression.
Regarding other areas of use for early chemotherapy, there is a presentation by Howard Sandler in the NRG group involving patients with locally advanced prostate cancer. Eligible patients were required to have any T stage, a Gleason score of >9, PSAs of <150 or 7/8 between 20 and 150, or T2s that were 8 or <20. The study consisted of two arms, one who were administered standard androgen suppression plus external beam radiation therapy, and one treated with androgen suppression for 24 months. For both arms, external beam radiation therapy followed six cycles of docetaxel. Surprisingly, data did show a 4% difference in overall survival, in favor of the combination arm (93% versus 89%). The combination arm also showed improvements in other areas, including biochemical failure, disease free survival (65% versus 55% at six years), and distant metastases at any time.
After reviewing the study’s data regarding death rates and causes, Dr. Petrylak recommends that this trial undergoes further observation before adopting docetaxel as a standard of care. Although the death rate is fairly low overall, and death due to cancer for patients in the combination arm is a low number – at seven deaths, the data shows two protocol-related deaths due to neutropenic sepsis for this arm. Death due to other causes is high in the androgen suppression plus radiation therapy arm, and death due to a second primary cause was higher in the hormone therapy plus radiation arm as well. Additionally, four patients in the chemotherapy arm had an unknown cause of death. This indicates that, although the data from the study shows promise, there is a need for further follow-up.
Dr. Petrylak then reviews findings from the SWOG 9921 trial, a phase III study comparing the effects of mitoxantrone combined with prednisone and androgen blockade versus androgen blockade alone. The survival rate data of this study has not yet been published, but it must be noted that the survival rates discussed mirror the patterns shown in the previously-mentioned trials. For high risk prostate cancer patients, the survival curves appeared to reach the same levels as in the other trials, although the event rate was low. Dr. Petrylak interprets this as a sign that more time may be required in order to recognize the extent of the difference, as the current general consensus is that mitoxantrone is effectively not the best drug for this disease.
Dr. Petrylak transitions to another trial, the TAX3501 study, a randomized, phase III, adjuvant study of post‐radical prostatectomy in high‐risk patients with prostate cancer, comparing 18 months of HT with and without docetaxel chemotherapy (either immediately or deferred). The patients underwent either androgen deprivation therapy, docetaxel, or observation, and then were subsequently treated with ADT or docetaxel progression. While there have been other attempts at studying adjuvant therapy after prostatectomy, this particular trial was closed due to lack of accrual.
A different trial that did have adequate numbers is the PUNCH trial, which compared radical prostatectomy alone versus neoadjuvant docetaxel plus hormones plus radical prostatectomy. This study, which was predominantly for patients with high risk localized disease, is currently closed and hopefully will provide helpful data in the near future.
It is important to determine why data shows such a profound difference with the earlier use of docetaxel. Data from the STAMPEDE trial as well as more recent data confirms that the clones that express ARV7 do respond to docetaxel. The cause of that may be that clinicians are eliminating those clones too early on, as the disease is biologically different. Dr. Petrylak interprets this information as confirmation that the problems seen in the European GETUG study can be attributed to trial design flaws. This may be an opportunity to conduct clinical trials in the earlier stages of disease, as there are other drugs such as abiraterone and enzalutamide that can be used earlier on.
As for future directions in this area of study, Dr. Petrylak sees merit in researching whether combining abiraterone and/or enzalutamide with docetaxel will generate the same results as the early administration of docetaxel but with less toxicity. Importantly, this may create an enhanced potential for side effects. such long term androgen deprivation or further androgen deprivation, as more patients are seeing early treatment with docetaxel, which means they may not necessarily have the performance status to receive it later on. This means clinicians must be extremely cautious of the care needs for these patients in future trials.
In conclusion, androgen blockade plus docetaxel is the standard of care for first-line metastatic prostate cancer. Physicians must assess whether it’s appropriate to give this treatment to patients in that setting by focusing on whether each patient is fit enough to receive, as it is unlikely that subsequent therapy affects the outcome.
Question and Answer Session
AUDIENCE: Regarding the GETUG study, when you mentioned the subsequent therapies that were administered probably in STAMPEDE and certainly in the American study, the GETUG study was at a time when a lot of those agents weren’t approved in Europe, so the follow-up on treatments may have been distinctly different between patients who failed.
PETRYLAK: Exactly. It’s certainly possible. And again these trials, remember that STAMPEDE started in 2005, so there’s a lot of variability that is seen in this so that’s a very valid critique. I think we’ll need to see a full analysis. This is where I think a meta analysis that’s properly done, not just simply pulling things from the clinical trials that are published, but actually taking the data sets and combining them. I think that’s where it’s going to be crucial.
SHORE: Dan, with regard to the presentation, this arm shows statistical significance of ADT plus zoledronic acid, would you recommend that? Or are you now going to think about that in patients who present with high volume androgen sensitive metastatic disease who are unfit for chemotherapy?
PETRYLAK: That’s a great question. You know the trouble is some of the legal implications of celecoxib in the United States. These drugs present cardiovascular issues as far as clots and other things. It wasn’t really seen in STAMPEDE but I think what you have to do is carefully select your patients and this is where being a good physician comes into play, especially with an elderly frail patient. I think you have a very valid point. I do believe the data because a number of years ago there was a push towards looking at some of these sundilac early on in metastatic prostate cancer and we did see some activity, and there is good preclinical data to support that.
CRAWFORD: So, do you recommend utilizing chemotherapy upfront in minimal metastatic disease because the study was severe and then the other two trials that had lesser disease did not seem to benefit?
PETRYLAK: Well, STAMPEDE did not separate it. So that’s the whole problem. STAMPEDE did not separate minimal from extensive. So what I’m telling people right now—
CRAWFORD: Locally advanced is looking at it.
PETRYLAK: Are you saying it should be given for locally advanced patients or just to—
CRAWFORD: No. I’m sort of putting minimal metastatic disease with locally advanced, which I guess you can’t, but if someone walks in, they’ve got 12 lesions on a bone scan and some pain, and then somebody has one lesion in the lumbar spine, both their PSAs are the same, everything else is the same. Would you give chemotherapy if the person has one versus 12 based on the data?
PETRYLAK: Based on the data, the answer is you really can’t ferret it out right now because the data on the CHAARTED trial is not mature and there are some reasons why it may not have also shown the difference. What I would do in that situation is talk to the patient, make them aware of the data, but I also would get a sense as to how rapidly their disease is progressing. A patient who presents de novo metastatic may be very different than the locally advanced patient who has a prostatectomy, has a 10-year gap, and they develop that solitary bone metastases. I think that’s something we have to also understand as well.
CRAWFORD: Most of those people probably have been on hormone therapy when they get it. I think the biggest damage being done is that you can’t neglect the 17 months survival benefit, but as you alluded to, when that trial was started that was it. Now we have five different new drugs. We have enzalutamide, we have abiraterone, we have new ones coming on. So to me, it seems like that we’re taking a step backward if we’re doing chemotherapy first. We’re creating a whole new thing we have to study now. People are going to docetaxel but the good thing is in a way, it doesn’t apply to a lot of people because there are not many with newly diagnosed metastatic disease. What are your thoughts? Don’t you think we should be using abiraterone/enzalutamide, etc., earlier rather than chemo?
PETRYLAK: We should be thinking about it in clinical trials. The trouble is, we don’t have the data yet. Again, mechanistically these are different. I was absolutely fascinated by some data that was presented at PCF this year, that if you give androgen back to patients the ARV7 clones disappear. So, is there something unique about Docetaxel in this situation that you’re delaying that particular emergence? You’re absolutely right. These drugs are active, we should move them up earlier but without the clinical trials, that’s an issue and again I think we’ve got to pay attention to toxicity. Because it’s not as if you’re giving these drugs for months, you’re now giving these drugs for a longer period of time and there may be a different toxicity, a very different toxicity rate seen for that longer period of exposure. So careful trials need to be done.