Full results of apalutamide in treatment of mHSPC

At the end of January, we had reported that the results of the TITAN trial — the Phase III trial of standard ADT + apalutamide (Erlead) or standard ADT + a placebo in men with metastatic, hormone-sensitive prostate cancer (mHSPC) — were positive, and that they were going to be reported at a meeting later in the year.

So the full results of the trial were reported by Chi et al. at the annual meeting of the American Society of Clinical Oncology (ASCO) earlier today (see here for the abstract and here for a media release issued by Johnson & Johnson).

The TITAN trial was a multi-center, randomized, double-blind, Phase III study. Patients with prior treatment for localized disease or prior docetaxel for metastatic, hormone-sensitive prostate cancer were eligible, and all patients received continuous, standard ADT together with either apalutamide (240 mg once a day) or a placebo. The primary endpoints for the study were radiographic progression-free survival (rPFS) and overall survival (OS).

Here are the core study findings:

  • Average (median) age of the patients was 68 years.
  • 8 percent of the patients had been given prior treatment(s) for localized disease.
  • 11 percent of the patients had received prior docetaxel chemotherapy.
  • The study follow-up period was 22.6 months.
  • follow-up, 66% of patients in the apalutamide group and 46% of patients in the placebo group remained on treatment.
  • Compared to patients who received treatment with a placebo, the patients treated with apalutamide had
    • A 52 percent reduction in risk of either death or radiographic progression
    • A 33 percent reduction in risk of death
    • A significant increase in time to initiation of cytotxic chemotyherapy (hazard ratio [HR] = 0.39)
  • Average (median) rPFS was 22.1 months for patients in the placebo group, but was not reached for patients in the apalutamide group.
  • Average (median) overall survival was not reached for patients in either the placebo group or the apalutamide group.
  • Rates of Grade 3/4 adverse events were similar in the two groups of patients:
    • 42 percent in the apalutamide group.
    • 41 percent in the placebo group.
  • Treatment discontinuation due to adverse events was low.
    • 8 percent in the apalutamide group.
    • 5 percent in the placebo group.

According to the investigators,

In the TITAN study in patients with metastatic castration-sensitive prostate cancer, including patients with high- and low-volume disease and prior docetaxel, addition of apalutamide to ADT significantly improved [radiographic progression-free survival] and [overall survival], and the safety profile was tolerable. These results support the addition of apalutamide to ADT for [the] treatment of patients with metastatic castration-sensitive prostate cancer.

Apalutamide is already approved for the treatment of non-metastatic, hormone sensitive prostate cancer (nmHSPC). On the basis of these data we would expect the US Food and Drug Administration (FDA) to expand the approval to include mHSPC some time in the near future.

12 Responses

  1. How can you account for such high grade toxicity almost equal in those treated vs. those on placebo ?

  2. This is good news for men with metastatic prostate cancer who might have been otherwise insurance coverage for Erleada because of questions about whether or not it can be useful in cases where a prostate cancer has already metastasized.

    I have recently published a paper in the on-line journal Oncogen with my mentor, Dr Donald Wheeler, that documented the effectiveness of Erleada in treating my metastatic Gleason 9 (5 + 4)prostate cancer when it was used as a monotherapy.

    One might argue that the TITAN study is more definitive because it used a placebo control and random assignment to treatment conditions. However, consider the limitations that such studies have:

    (1) Even if you can be accepted into the trial, you have only a 1 in 2 chance of receiving the Erleada.

    (2) You are required to continue to take a medication that already had stopped working, thereby ensuring exposure to possible side effects from both medications.

    (3) I knew that Erleada produced a dramatic reduction in my PSA immediately after I started taking it and did not have to wait until the code was broken to find out whether I was in the active arm of the treatment protocol.

    These comments are not meant to cast aspersions on the so-called gold standard in treatment research. Each type of design asks a different question and provides different types of information. The TITAN study demonstrated the effectiveness of Erleada on average for men with metastatic prostate cancer compared to a placebo-controlled condition. My study asked if Erleada would work for me, using my previous response to five different treatment conditions as multiple baselines to establish confidence that the results were not due to random fluctuations in my PSA levels.

    Only 11% of the men in the TITAN trial had had “local therapy” so it is not clear from those results if Erleada would be effective for someone like me who had failed to respond to both surgery and radiation.

    I hope that more single case research designs are used in the future to study the effects of Erleada as a monotherapy using the research data analytic procedures Don and I described in our article.

  3. Dear Bob:

    If you look at the media release issued by J&J your will see that it gives greated detail about the adverse effects as follows:

    “The most common Grade 3 AEs for ERLEADA plus ADT versus placebo plus ADT were hypertension (8.4 percent vs. 9.1 percent) and skin rash (6.3 percent vs. 0.6 percent).1 Additional reported Grade 3 AEs for ERLEADA plus ADT versus placebo plus ADT were back pain (2.3 percent vs. 2.7 percent), blood alkaline phosphatase increased (0.4 percent vs. 2.5 percent) and anemia (1.7 percent vs. 3.2 percent). … Rash of any grade was more common among patients treated with ERLEADA plus ADT, versus placebo plus ADT (27 percent vs. 9 percent, respectively).”

    I have no explanation for the apparent overall similarity of the “toxicities” of the two forms of treatment. All I can do is report the data. I do agree with you, however, that this level of side effects in both arms of this trial does raise questions.

  4. Dear Al:

    Much as “n of 1″ studies can offer us detailed insight on the way individuals with a specific medical history respond to specific forms of therapy, you need to bear in mind that (based on the data from the TITAN trial) there are just as likely to have been one or two men with a history similar to yours enrolled in the TITAN trial who did not respond well to Erleada.

    The problem with all “n of 1″ studies is that that is exactly what they are: detailed case studies in one specific patient. There is no way that regulatory agencies like the FDA (or payers) are going to be able to use such data to make decisions about drug approvals or coverage of treatment with specific agents in a disorder like prostate cancer.

    Even when we are dealing with very rare disorders, studies required for product approval and “value” are usually based on something like n = 10 or n = 20 patients as compared to historical controls.

    Also, when you wrote that “You are required to continue to take a medication that already had stopped working, thereby ensuring exposure to possible side effects from both medications”, that was inaccurate. The patients who were enrolled in this trial were either ADT-naive or had been on ADT for a short period and were still responsive to this treatment. And every patient had the right to withdraw from the trial at any point in time for any reason. No patient was “required” to stay on a medication that had stopped working. That would be unethical.

  5. For metastatic, hormone-sensitive prostate cancer guys – is there much of a difference between side effects and benefit of adding Xtandi vs Erleada to hormone therapy? And I realize there would be insurance challenges, but I’m just wondering which would be more appropriate.

  6. Thanks for your thoughtful response, Mike.

    Scientific research can be broadly categorized as falling into one of two categories: nomothetic research seeks to establish general relationships between variables by studying large numbers of subjects, while ideographic research does exactly what you suggest. The N = 1 studies try to determine if there is a functional relationship between two variables by studying in greater detail the history of an individual’s response to treatment.

    The TRITON trial was designed so that individuals received Erleada with another ADT agent so that no one fitting my circumstances would have participated in that trial. However, I accept your general point that there probably are people who have not responded favorably to using Erleada as a monotherapy.

    Ideographic science will advance our understanding of why that is the case by retrospectively identifying groups of responders and non-responders to determine what factors the responders share in common that differentiates them from non-responders. Then it will be possible to test that hypothesis by conducting an appropriate between groups comparison design. However, look at the practical benefits of conducting idiographic research before conducting the nomethetic study.

    A group of people will benefit from taking Erleada without being exposed to the side effects of another medication. Furthermore, for subjects taking Erleada plus another ADT agent not much is available other that chemotherapy when that combination stops working, whereas people taking Erleada as a monotherapy may derive some benefit by adding the ADT agent at that time.
    Perhaps by then better alternatives will be available.

    Once we give up the notion that we are trying to cure our cancer by looking for magic bullets and recognize that it is essentially a systemic disease that requires long-term management, then our strategy for sequencing treatments changes accordingly.

    I am not saying that monotherapy is always preferable to using combinations of treatment.
    In an earlier commentary you presented and analyzed evidence suggesting just the opposite — that instead of using surgery or radiation as single therapies it seems to be more effective to combine them, perhaps with a hormone treatment like Casodex.

    I understand that in Europe it is considered standard practice to use Casodex immediately after surgery rather than wait for a biochemical recurrence. In retrospect, I wish I had done that but hindsight is always 20/20.

  7. I hadn’t seen Bob’s query before I posted my response.

    First, let me say I hate SpellCheck and regret the apparent “typos” in my earlier reply.

    Remember that “placebo” in the Erleada trial consists of an ADT medication plus a placebo. Therefore, not all of the side effects come from the “placebo”
    In cases where the “placebo” had fewer side effects than the experimental treatment, that could be an artifact of the experimental design or it could indicate that the “placebo” attenuated the side effects of the ADT agent the person was taking.

  8. Dear Jerry:

    We don’t have a “formal” answer to that question because we don’t have any “head to head” data, but the chances are that the effects and the outcomes would be very similar.

  9. Dear Al:

    I think you need to understand that trials like the TITAN trial are not done “in a vaccum”. Long before anyone designed the TITAN trial, there had been much smaller open-label studies of the potential uses of apalautamide (just as is the case for almost every other drug as it goes through the development pipeline). These studies border on being N of 1 studies and are inteended to do exactly what you describe: work our the most likely dose of a specific drug that will be effective and safe (either alone or in combination with other drugs).

    The reason that drugs like apalutamide and enzalutamide are used in combination with ADT is because there is still a general consensus that this is the best way to use them when they are used to treat men with metastatic prostate cancer. When bicalutamide (Casodex) is used alone at the 150 mg dose in Europe, it is in men who are not metastatic in order to delay the onset of metastasis, and my suspicion is that we may start to see large trials to proved the value of drugs like apalutamide and enzalutamide in that setting in the not too distant future.

    And by the way, it is by no means “standard practice” to use bicalutamide in that way after surgery in Europe. It is an option for the treatment of specific subsets of patients, and it comes with risk for a potential set of side effects (specifically including gynecomastia) than many men might prefer to avoid.

  10. Dear Al:

    There is no way that a placebo, when given in combination with ADT, is going to attenuate the side effects of the ADT. Placebos have no therapeutic or pharmacological effect whatsoever. That’s why they are used as placebos.

    The placebo in the Erleada trial was an inactive tablet that looked just like the Erleada tablet, but it had no pharmacological effect. The ADT was not part of the “placebo”. It was a set of therapeutic options (either surgical castration or an LHRH agonist) that were going to have the same effects (suppression of testosterone levels) in all patients, regardless of whether a patient was renadomized to treatment with apalutamide or the placebo.

  11. Not sure if this got through or if you chose not to respond, so I will try again.

    With all due respect, Mike, you are using an outdated concept of a placebo — one which was promulgated by the pharmaceutical companies as a convenient way for them to test the effectiveness of their medications. Check out the book Cure: A Journey into the Science of Mind over Body” by Dr Jo Marchant, who has a PhD in genetics and medical microbiology.

    She documents the effectiveness of placebos in treating a variety of medical conditions and page 9 of her book summarizes the results of a meta-analysis of 53 controlled trials where placebo. treatment in the form of “sham surgery” was contrasted with results obtained for promising surgical procedures for conditions ranging from angina to arthritic knees. Sham surgery was found to be just as effective in half of these studies!

  12. Dear Al:

    I am highly familiar with what is known as “the placebo effect”. The fact that people have “responses” to treatment with placebos is extremely well understood, and is based on an extensive literature. However, that doesn’t make the need for the use of placebos in clinical trials any less important. In fqct, most researchers would tell you that it makes their use more important.


    Because then one knows that the psychological effect of having received treatment when no treatment with demonstrable clinical effectiveness was given has been allowed for.

    I am sorry but I think your perspective on this issue is entirely misplaced. On top of which, it wasn’t the pharmaceutical industry that came up with the idea of using placebos in clinical trials anyway.

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