Early docetaxel chemotherapy + ADT extends survival of men with metastatic prostate cancer

According to a media release issued yesterday by the National Institutes of Health, the CHAARTED clinical trial has shown that men with hormone-sensitive, metastatic prostate cancer who received docetaxel chemotherapy at the start of standard androgen deprivation therapy (ADT) lived longer than patients who received ADT alone.

Obviously we do not have complete detail on the results of this trial as yet. However, here is what we do know according to the media release:

  • The study enrolled 790 men with metastatic prostate cancer between July 2006 and November 2012.
  • All patients started treatment by receiving androgen deprivation therapy (ADT).
  • Men were randomized to treatment with either ADT alone or ADT + docetaxel-based chemotherapy every 3 weeks over a period of 18 weeks.
  • Approximately two-thirds of patients enrolled had a high extent of disease (i.e., their disease had spread to major organs such as the liver, had a spread resulting in four or more bone lesions, or both).
  • Average (median) follow-up to date is 2 years.
  • The projected 3-year overall survival data were
    • 69.0 percent for men randomized to ADT + docetaxel-based chemotherapy
    • 52.5 percent for men randomized to receive ADT alone
  • The projected 3-year overall survival data for the men with a high extent of metastatic disease as defined above were
    • 63.4 percent for men randomized to ADT + docetaxel-based chemotherapy
    • 43.9 percent for men randomized to receive ADT alone
  • The study’s independent Data and Safety Monitoring Committee recommended that the study results be made public because this planned interim analysis showed prolongation in overall survival.

The media release states that:

because [docetaxel] is a chemotherapy drug associated with some toxicities, its use in combination with ADT at this time should be restricted to patients with high-extent metastatic prostate cancer who are candidates for treatment with docetaxel, according to the trial investigators. This is the group of patients who experienced the most benefit in the current analysis. Further follow-up will be performed on patients with less extensive metastatic disease who participated in E3805 in order to define the effect of this treatment combination on these patients.

To quote the principal investigator, Christopher Sweeney, MD, of the Dana Farber Cancer Institute in Boston.

The results of this study are practice-changing. We have strong scientific evidence that patients with the most advanced metastatic prostate cancer benefit from the early addition of docetaxel to ADT and not waiting until the cancer has progressed on hormonal therapy. The findings of this study are important both for improving the clinical care we deliver now and in designing new clinical trials as we strive to further improve the lives of men with metastatic prostate cancer.

Clearly these data are going to have significant impact on the management of metastatic prostate cancer because they imply that men with a significant extent of metastatic disease will now start to get docetaxel-based chemotherapy much earlier in the course of their disease than previously. This will also have implications for the use of drugs like sipuleucel-T, abiraterone acetate, enzlautamide, and others. Furthermore, it implies that men with “high extent” metastatic disease will need early referral to a medical oncologist with experience in the management of docetaxel-based chemotherapy (since urologists have little to no experience in this area and the majority do not have any familiarity with infusion-based therapies of any type other than bladder infusions of BCG in the management of bladder cancer).

The “New” Prostate Cancer InfoLink will be interested to see if more details from this trial will be available by the time of the Genitourinary Cancer meeting in San Francisco at the end of January or whether we shall have to wait until the ASCO meeting in Chicago in May/June.

17 Responses

  1. This is a huge finding and now needs to be explained to all men with more advanced metastases. The question is whether the FDA will now extend the indication for docetaxel. This result will increase the number of questions needing answers, such as what to do about abiraterone and enzalutamide. If both become approved pre-chemo, is the next question whether men should get abiraterone or enzalutamide along with the docetaxel?

  2. Any thought on how this finding may pertain to some one who is castrate resistant and had early docetaxel?

  3. Well, but did patients who progressed after ADT and whose cancer became castrate resistant, start docetaxel after they progressed in this study?

    It should be of no surprise that in metastatic patients docetaxel and ADT beats ADT alone, assuming no other treatment is given to either group. But normally, men who progressed after ADT would receive docetaxel anyway.

    Did the study take this into account?

    Basically, if the study said combined ADT and docetaxel are better than first ADT and then docetaxel, it would be major news. But I don’t see it anywhere explained like that …

  4. Bill:

    I haven’t got a clue … and frankly I doubt if anyone else does yet either!

  5. Dear Pawel:

    You are asking for data about a second study that probably now needs to be done. The CHAARTED trial wasn’t designed to answer the question you are asking.

  6. Very interesting data … before we draw conclusions we need to consider other studies in the field too: a French GETUG trial was negative and the British trial (STAMPEDE) has recruited patients but results are still pending.

  7. For Bill Manning and others, “The interval from the last cycle of docetaxel-based chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer.”
    For men who had early chemo, if there is a longer period (years) until chemo is re-instituted then chemo effective the second time.

  8. Dominik’s point is a good one we discussed today at SWOG. There is a specific subset of patients that benefitted greatly in this trial. How that affects other trials is unclear. S1216 by SWOG is one current trial includes this subset of patients. Our discussions today are to move slowly. We feel that S1216 will stay alive as a result of CHAARTED based on the fact that many patients won’t want to be in a hurry to start chemotherapy. In addition, we are looking at allowing an arm to S1216 for chemotherapy patients qualified by the CHAARTED study findings to still have that option while still studying the CYP17 drug TAK700.

    In any case. This is a good announcement by ECOG-ACRIN. It appears that for extensive mets these patients should start chemo at the same time as ADT as opposed to waiting for ADT to fail.

  9. Just a follow up …

    We (SWOG) are meeting by teleconference tomorrow to discuss exactly what Dr. Chodak asks. One step further as well. Should trials studying early enzalutamide and abiraterone that currently have this patient subset be modified to allow for docetaxel? I mentioned S1216 before but there are many of these studies out there. Stay tuned. SWOG has set up special teleconferences to discuss its trials, and I am certain the other cooperative groups are doing the same. We are working with ECOG-ACRIN on these topics. I think the obvious question is if primary ADT and docetaxel work this well in early settings, will the results be even better along with other second line HT drugs in that same early setting? But that re-designs the trials.

    A second problem comes along with many existing trials being able to accrue if this patient subset is taken away by the findings of the CHAARTED trial. It could severely hamper these trials’ results.

    Game changing indeed.

  10. Tony:

    Has SWOG addressed the issue raised by Pawel Czekanski, i.e., whether immediate use of ADT + docetaxel + prednisone actually offers a real survival benefit compared to ADT followed by docetaxel + prednisone at the time of onset of castration resistance?

    This question also raises the question of whether immediate ADT + docetaxel + prednisone offers a real survival benefit compared to ADT followed by enzalutamide or abiraterone acetate at onset of castration resistance, and then docetaxel + prednisone when the abiraterone and/or the enzalutamide fails.

  11. Mike,

    The answer is ~ I don’t know. But I’ll ask in tomorrow’s teleconference (Wednesday). I’ll respond here with that answer. But that is the idea here with the CHAARTED trial ~ to try to determine when might be the better timing for chemotherapy. But after the trial period how long men live is not clear. I will have better access tomorrow to some of the trial doctors and will certainly ask. As far as what this trial tells us, we know that early chemotherapy with ADT is better than ADT alone. Because we know that many patients can leave a trial for a proven therapy, I have to assume that as patients progressed in the ADT-only arm that at some point they had access to docetaxel + prednisone after refractory conditions were present. But that is an assumption until I see the paper.

    Your second point is also not part of the question in this trial. We have enzalutamide + abiraterone + prednisone trials that are getting started and what effect the CHAARTED trial results might have on that patient pool is not clear. The trials in some of these settings is pre-castration and post-castration refractory. In these settings there are three very effective mechanisms that could work together in extreme cases … but the effects of the toxicities of all three of these drugs together at once remains unclear.

    Lot’s of questions still to ask…

  12. Thank you Tony.

    One problem with the CHAARTED trial, as I see it, is the short follow-up period, and (potentially) the fact that we have no idea what other forms of therapy men went on to take after they failed ADT. A second problem is that this trial was not blinded. In other words, the men and their doctors all knew who was getting chemo and who wasn’t. In and of itself, this can have effects on trial results — which does not mean that I see a simple way around that problem. Asking people go to the clinic to receive infusions that might be a placebo (i.e., a saline solution) presents its own issues.

  13. Mike:

    You are spot on with the time frames. But we do know the standard of care was in place for the ADT arm. They did get the option of delayed docetaxel and survival was better in the “adjuvant” setting.

    Speaking with the group, more time is needed in the follow-up and the trial PI is monitoring for several years to come. But here’s the answer for Pawel:

    This trial absolutely confirms that immediate docetaxel is better than the standard of care of ADT followed sequentially by docetaxel. Our biostatistician said that it is important to recall the patient subset of more more extensive metastases and a 2-year window. Immediate is better than delayed, or sequential, chemotherapy in terms of both progression and survival in the more advanced patient.

    Have a look at the media release from ECOG-ACRIN.

    Caution: We still need more time and are eagerly awaiting ASCO 2014 for released data. There was excitement on the call, however. For now, no changes in trials at SWOG. We are in confidentiality on the actual data but our statisticians have seen the data and remain “positive”.

    I hope this helps.

  14. I have prostate cancer and saw the effects of chemotherapy, radiation and prostate cancer on a close friend who recently died followng 3 years of treatments. My specific comment is that research should include data on the impact of the treatment on quality of life. How does the treatment affect sleep, sex, particpation in sports, energy levels, ability to eat or keep food down, or walking? Living longer is good, but living good is so important.


  15. Dear Barry:

    The Prostate Cancer Roundtable agrees with you, which is one of the reasons it just made a significant modification to its national policy agenda.

  16. I am a person who had chemo up front with Taxotere while on Lupron and Casodex. I was diagnosed with metastatic prostate cancer to the para-aortic lymph nodes. I was basically put on Taxotere in July of 2003 and did three rounds of Taxotere (4 weeks on; 2 weeks off); they added estramustine to the Taxotere.

    I was diagnosed in March of 2003 and some doctors were giving me a life expectancy of 3 years. Well I am now approaching 11 years and have an undetectable PSA. I am currently on Firmagon (degarelix) plus Casodex. I also was off of all hormone blockade for almost 6 years before it started to come back and my PSA went up to 25. Lupron brought the PSA level down yet the serum testosterone (T) level was still at 75 ng/dl, so they changed me to Firmagon and now both my PSA and my serum T are undetectable. So I am a huge believer in chemo up front. My doctor here in Green Bay said that none of his patients had lived as long as me with metastatic prostate cancer. He believes it is due to the fact that I had chemo up front.

    Fortunately for me I was entered into a early study group at the University of Colorado Hospital (UCH) under the care of E. David Crawford (UCH), Dan Petrylak (Yale now and before at Columbia, NY), and Mike Glode (UCH). This was while the drug was still in clinical trials.

    So I would say that I am living proof of the fact that up-front treatment is good. I am a lucky one. I ran the prostate cancer support group at UCH for almost 7 years and I watched a lot of my people die. I believe that chemo up front just like they do for breast cancer is the way to treat advanced prostate cancer. I think waiting until the guy has failed everything else is too little too late. Also, I was only 49 at the time and had a PSA of 19.8 and a Gleason of 7 (all 12 cores positive) plus distant metastasis that was verified with a CT-guided needle biopsy. So it was all over. Yet here I am, still alive and doing well.

    Thank God for my doctors and for being fortunate enough to still be here.

    All the best and good luck to all.

  17. Hello again from John F. Sharp who had Taxotere up front and is still alive 11 years later when given a prognosis of 3-year survival.

    Why should men be treated differently than women with breast cancer? They get Taxotere up front, yet we wait on men to start failing and when cancer has taken it’s death grip on them. I feel the same approach to the way breast cancer is treated needs to be taken into consideration with men with advanced prostate cancer. I was given 3 years by many doctors and I am the lucky one who is still alive and responding to now Firmagon plus Casodex. Should I donate my body to science so you can see for yourselves when I die? Bottom line: I believe in up-front treatment with chemotherapy, not when a man is weak and dying. That is just a nail in the coffin.

    I am a patient and not a doctor, yet I have learned a great deal in 11 years running a support group and watching many young men die. I am all about up-front treatment. Enough said. Thank God I had the doctors that I had: E. David Crawford, Dan Petrylak, Mike Glode. Without them I would not be here. I am from a long line of doctors in my family even though I am not one. I feel up-front chemotherapy is the way to go with advanced cancer — while the patient is still in good shape. Those are my two cents — for whatever they are worth.

    God Bless to all and keep on researching. You can reach me at my e-mail address. I will be more than happy to respond. I am alive.

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