Join Joseph Ischia and Ian Vella as they discuss all things enzalutamide with special guest, Neil Fleshner.
Neil Fleshner is a surgeon and clinician scientist and an established leader in the field of cancer prevention. He holds the Martin Barkin Chair, Division of Urology at the University of Toronto and is a Professor in the Department of Surgery at the same University. Additionally, he is Staff in the Division of Urology at the University Health Network and Princess Margaret Hospital in Toronto, Canada and holds the Love Chair in Prostate Cancer Prevention at the Princess Margaret Hospital.
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Talking Urology podcast transcript
So you’re gonna . . . start a patient on enzalutamide
JOSEPH: Hello. I’m Joseph Ischia and welcome to another episode of So You’re Gonna, a podcast from the team at Talking Urology where we are empowering doctors to develop a deeper understanding of the literature to ensure we apply the right evidence to the right patient. So you’re going to start someone on Enzalutamide. Today, I am joined by my co-host Ian Vela, and with the help of our international expert Neil Fleshner, we are going to give you everything you need to know to start someone on Enzalutamide and continue to monitor them.
IAN: Thanks, Joseph. We’ll look at all the latest news and evidence on Enzalutamide so you will be fully up to speed when that patient walks through your door this afternoon with metastatic castration resistant prostate cancer and one day, possibly more depending on the results of ENZAMET and ARCHES.
JOSEPH: But first, these podcasts would not be possible without the support of our sponsors. So we’ll be right back after a quick word from our sponsor.
SPONSOR’S AD: This podcast is supported by Astellas Pharmaceuticals Australia. Astellas has a long history in Urology with a number of products to treat lower urinary tract symptoms (LUTS), Over Active Bladder (OAB) & Prostate Cancer. Combining cutting-edge technology and innovative discovery platforms, they develop targeted treatments and support solutions to improve the standard of care for patients around the globe.
JOSEPH: Welcome back. We are grateful for the support of our sponsors, and I can assure you they had no say in the editorial content of the podcast but they did give advice on the regulations around discussing Registered Products in Australia. And as I mentioned, we are very lucky to be joined by our international expert, Neil Fleshner, a great friend and colleague of ours in Australia, who is helping us explore the role and benefits of enzalutamide and despite the fact he needs no introduction, I’ll let him introduce himself.
NEIL: My name is Neil Fleshner and I am a uro-oncologist in Toronto Canada, and I am the Martin Barkin Chair of urology at the University of Toronto and I work clinically at the Princess Margaret Cancer Centre.
JOSEPH: Neil is going to give us some great tips and tricks on how to use enzalutamide and look after men with castration resistant prostate cancer, but first let’s take a look at how the drug works and the big four studies that currently define its indications.
IAN: Let’s start by taking a look at enzalutamide. It is a rationally designed oral androgen receptor inhibitor and for those of you who have just woken up from a 10 year coma will know it as MDV3100. Enzalutamide was developed by Charles Sawyers who I worked with at Memorial Sloan–Kettering Cancer Center, and Michael Jung, when they were at the University of California, Los Angeles. It was approved by the Food and Drug Administration for the treatment of metastatic castration-resistant prostate cancer in the United States in August 2012 and for the treatment of non-metastatic castration-resistant prostate cancer in July 2018. When it first burst on the scene, it was called a novel anti-androgen because it had several distinct advantages over the other available anti-androgen agents at the time. It has three anti-androgen mechanisms of action: firstly, and most obviously, it inhibits binding of dihydrotestosterone to the androgen receptor and it does this with an 8 fold greater affinity than bicalutamide. Secondly, it inhibits nuclear translocation of the androgen receptor. That means that the androgen receptor, which is usually sitting in the cytoplasm waiting to bind with dihydrotestosterone, binds enzalutamide and is therefore unable to cross the membrane of the nucleus to get to the DNA where it would usually acts as a transcription factor; and thirdly, if the androgen receptor does get in to the nucleus, enzalutamide inhibits it binding to the DNA and prevents coactivator recruitment. Another advantage of enzalutamide is that it has no known agonistic effects. This is different to bicalutamide and the other first generation antiandrogens which may become androgen receptor agonists and actually stimulate a mutated androgen receptor.
JOSEPH: Wow. Ian. That is some serious hardcore knowledge. You know, if there’s one thing we love in Talking Urology, its…..
IAN: (sounding like he is interrupting) Holidays?
JOSEPH: Well, yes. Now that you mention it. But I was going to say basic science. Wait, let me just shut down Tripadvisor so I am not so distracted. Because it is basic science where this story begins. It is the continued stimulation of the prostate cancer cells despite castrate levels of testosterone that represents a transition to the lethal phenotype of castrate-resistant prostate cancer. This state is now recognised in most cases to be still driven by the androgen-receptor. There are multiple mechanism which would make a fascinating discussion for another day, but suffice to say that we have come a long way since we called it hormone refractory or androgen independent prostate cancer. I did my fellowship with Martin Gleave who tells a great story of how for many years researchers were looking at these resistant prostate cancer cells and they could not explain why they could still see the androgen receptor in the nucleus as if it was still active. But at the time, everyone was on board with Charles Huggins that castration sent the testosterone to zero and therefore how could it be that the androgen receptor that was driving these cells. Now we know about the multiple pathways that drive castration resistant prostate cancer such as receptor overexpression, promiscuous receptors, ligand binding domain mutations, and persistent receptor activation just to name a few. As mentioned above, Enzalutamide was first described in 2006 and was introduced for the treatment of prostate cancer in 2012, the same year Barack Obama got re-elected and the James Bond film series celebrated its 50th anniversary and released its 23rd film, Skyfall.
The majority of evidence in favour of this drug comes from the big four studies, namely the AFFIRM study, the PREVAIL study, the TERRAIN study and the PROSPER study. Now, IAN, I know it sounds like the latest line up of Ford SUVs, but they’re actually really big and famous prostate cancer papers. So with no further ado, let’s take a look at the papers:
IAN: I’d be delighted Joseph. And for the record, I drive a Holden Colorado 7. Let’s kick this party off with the AFFIRM study. It was the first major study we saw of enzalutamide and it was published in NEJM in 2012. This looked at the effect of Enzalutamide on survival in men with castrate-resistant prostate cancer after docetaxal chemotherapy. What it demonstrated was that Enzalutamide significantly prolonged survival in these men by nearly 5 months from 13.6 months in placebo to 18.4 months with enzalutamide.
JOSEPH: Absolutely right Ian. Enzalutamide caused a 37% reduction in the risk death.
IAN: So by now the Enzalutamide ball was really rolling, and by rolling, I mean forward to earlier stages in the disease timeline. Next up came the PREVAIL study, published in NEJM in 2014, which looked at Enzalutamide before chemotherapy. I find this is the best way to remember it: PREVAIL was PRE-chemo and AFFIRM after-chemo – easy huh?.
JOSEPH: And in this study enzalutamide significantly reduced the risk of death by 29% over placebo.
But as they say, there is more to life than just dying, or progressing radiographically, or delaying chemo, or decreasing your PSA by 50%, as the old saying goes; tell me about the risk of side effects?
IAN: True. After adjustment for the length of exposure, Enzalutamide had a higher risk of hot flushes, hypertension and falls. An adverse event ≥ grade 3 was reported in 43% of Enzalutamide patients vs. 37% of placebo patients.
JOSEPH: Just on that point, and this is a great example of what we can miss if we only read the headlines, is that while the rates of grade 3 or 4 adverse events appears similar in both groups, the median time until the first severe adverse event was 22.3 months in the enzalutamide group and only 13.3 months in the placebo group. So they are actually on the active drug for longer with more opportunity to have an adverse event which is actually delayed. Also, importantly, one patient in each group had a seizure. And, 6% in each group discontinued treatment because of an adverse event. Alright, IAN, we started out this podcast by saying that enzalutamide was better than the first generation anti-androgens that were out there. This was explored in the TERRAIN study.
IAN: In 2016 in The Lancet published the TERRAIN study. This directly compared Enzalutamide to Bicalutamide in men with asymptomatic or mildly symptomatic metastatic castrate-resistant, chemo-naive prostate cancer. Again, Enzalutamide was comfortably the better option for the treatment of these men. Patients treated with enzalutamide had significantly improved median progression-free survival with a hazard ratio of 0.44, i.e. 56% less likely to progress at any time point in the future.
IAN: Enzalutamide also conferred improvements in quality of life despite the higher rate of serious adverse events that were reported by 31% of Enzalutamide patients vs. 23% of Bicalutamide patients. So in summary Joseph I would ask, why would you continue to drive a Model A Ford (i.e. bicalutamide) in this setting and leave a Ferrari (enzalutamide) in the garage? It doesn’t seem to make a lot of sense to me personally?
JOSEPH: When talking about enzalutamide, there are always two things we are interested in: the rate of fatigue and seizures. In this study, fatigue occurred in 28% of enzalutamide patients compared with 20% of bicalutamide patients, with severe fatigue similar in both groups. And the number of seizures due to treatment was 1 in each group. So tell me, IAN, what is the final off-roading study in the line up of big enzalutamide trials?
IAN: Well now you’re talking about PROSPER, a study published in the New England Journal of Medicine in 2018 where enzalutamide has been rolled even further forward to men with nonmetastatic castrate-resistant prostate cancer.
JOSEPH: PROSPER? It doesn’t sound very rugged for a 4 wheel drive. But it did compare Enzalutamide to placebo in men with nonmetastatic castrate-resistant prostate cancer on standard imaging of CT and bone scan and a rapid PSA doubling time of ≤ 10 months. The primary endpoint was metastasis-free survival. Ian?
IAN: The median metastasis-free survival was 36.6 months in the Enzalutamide group vs. 14.7 months in the placebo group. Overall, Enzalutamide led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo.
JOSEPH: Let’s just pause for a moment to make an important point about enzalutamide indications for use. While this study was published in the New England Journal of Medicine late last year, we must stress that enzalutamide is not currently approved for use in Australia in men with non-metastatic castration resistant prostate cancer.
IAN: That is a good point and Joseph, what do you make of this non-metastatic prostate cancer space?
JOSEPH: This definition is based on standard imaging of CT and bone scan. So you can ignore those lymph nodes in the pelvis and those pesky purple/yellow spots on the PSMA scan if you want to put a man in this category.
JOSEPH: So overall, these figures we have been discussing are pretty impressive when you read the papers, but remember that in today’s world, the comparator option in this group of metastatic castration resistant prostate cancer patients is not really placebo, it should actually be chemotherapy or abiraterone. No randomised head to head trial of these agents has ever been done, and probably never will be, but a lesser podcasters would say that the hazard ratios in these trials are actually quite similar. So if we don’t have randomised trials that inform us one what to do or which drug to use, how do we decide which one to use in newly diagnosed metastatic castration-resistant prostate cancer?
IAN: Well that is the billion dollar question! I think there are three key factors:
- What is approved for the clinical setting and reimbursed in your country,
- Physician experience, and
- What is going to be best tolerated and accepted by your patient.
JOSEPH: Hey! nice Home Alone reference – I love that movie! OK so, you’ve convinced me that Enzalutamide works, but as is always the case in medicine, that is only half the story. Or to put in another way, it’s not just what goes in to the patient, it’s what comes out. So Ian, let’s make the correct assumption that you like treating men with advanced prostate cancer. Who would you want to treat?
IAN: then I would look for men with metastatic castration resistant prostate cancer . While it is not yet currently approved in Australia, there are some parts of the world where you can also look for men who are pre-chemo non-metastatic by conventional imaging. In Australia they will also either need to be either post chemo, intolerant of chemo or have predicted intolerance to chemo to get approval. This man needs to have a castrate testosterone, a rising PSA on at least two tests a month apart, and be fit enough to tolerate the treatment and live long enough to get a benefit- all men in the trials were at least ECOG 1 or 2 which means they are active and take care of themselves. The dose to be taken is 160mg daily which is four 40mg tablets. So as you can see, it’s not rocket science.
JOSEPH: We asked Neil what he takes in to account when he is thinking of starting treatment in men with metastatic castration resistant prostate cancer. You may hear some restaurant sounds in the background. Take it away Neil.
NEIL: Well, first I’ll say that if you think about Enzalutamide and Abiraterone, certainly from the urologists point of view; even though both drugs have a low prevalence or incidents of toxicity, there is no doubt that Enzalutamide is easier to manage in the office. The burden for the urologist is quite minimal, so what do we do? First of all, it’s important to be aware of the absolute contra indications of the drug, so certainly patients with a history of seizure or conditions that put them at a risk for seizures such as prior head injury, prior brain surgery, prior stroke, were not included in our pivotal trials and there is about a 0.8-0.9% risk of seizures. So patients who have that risk should really not be placed on that drug. That’s really the only absolute contra indication to using the drug.
JOSEPH: What baseline investigations does Neil do before commencing enzalutamide?
NEIL: So, in terms of baseline evaluation, really it just involves a typical analysis that we do on all our patients with CRPC. Periodic monitoring of PSA, testosterone, phosphatase as well as just clinically examining the patient. Really these are related to the disease more than the drug in the context of Enzalutamide which would not be true about Abiraterone where you have to monitor liver function and potassium because those can be affected by that particular compound.
IAN: And once he starts enzalutamide, we asked Neil how often he monitors these patients in his rooms.
Neil: In terms of frequency of visits, I typically see my CRPC patients every 4-6 weeks, mostly because of the disease itself. Certainly Abiraterone requires a monthly follow up. But in reality, the patients need to be seen every 4-6 weeks because the disease itself almost mandates it. They can get sick quickly, they can regress quickly. Just giving them a 3-4 month prescription and say come back and we’ll see you to me means you don’t really understand the disease. So, you have to see these patients frequently. In terms of monitoring, the major adverse effect, aside from the rare risk of seizure, is hypertension. There is about a 10-15% risk of that, so patients need a blood pressure check and certainly I manage that, or you can have the family Dr manage that. Aside from that, I should mention that Abiraterone has a similar rate of hypertension. Aside from a blood pressure check, it tends to be quite a quick visit in the urologists office.
JOSEPH: When you prescribe this drug, there are a number of side effects that you need to keep an eye out for. Firstly, and probably most commonly, there is the issue of weakness and fatigue that affect about 30% of men. How does Neil recommend we can manage this?
NEIL: First of all I’ll say that there is no doubt that patients in this state of cancer have fatigue. Many of them have been on hormones for years and many of them come in tired. I think Enzalutamide induces fatigue but so does Abiraterone. It may be a bit higher with Enzalutamide, although this hasn’t been born out in many phase 3 trials. To manage the fatigue, typically I do it by really life style modifications. I encourage patients to be active. In some cases I encourage them to use an energy drink like Red Bull, which has caffeine. But, that’s really it. You know, we always want to pre-condition them that fatigue may occur. Really in the vast majority of patients, it shouldn’t be an impediment to using the drug and of course in patients with extreme fatigue, sometimes I will dose reduce the drug and in some cases I will swap them to Abiraterone; but I can’t say necessarily that that manoeuvre actually improves their fatigue. I have limited experience with this.
IAN: Patients should be advised to exercise as part of their prostate cancer treatment and this is whole another podcast coming soon. Other common side effects are 20% of men complain of hot flushes while 10% complain of headaches, and as Neil mentioned, hypertension can be common. There are rarer side effects and I recommend you go to the show notes for this podcast at www.talkingurology.com.au for the full list.
JOSEPH: It is important that patients should be encouraged to report side effects. If side effects are disabling for the patient, and they can be with 6% of men needing to discontinue enzalutamide due to side effects, there is an alternative treatment exists in the form of abiraterone so patients should be made aware of this drug too so they don’t downplay side effects for fear that their treatment will be discontinued and with that one of their last resorts in their fight against prostate cancer.
IAN: And finally, we asked Neil what he thought was one of the key mistakes he sees doctors making when prescribing enzalutamide?
NEIL: I think the key thing is timing of therapy. As these drugs have been looked at, certainly if you look at the results from the prevail trial, if you look at the results of even the ‘Prosper’ trial most recently; I think the key take home message is you want to try and get patients on these drugs earlier rather than later. Certainly if you are going to wait until they are symptomatic, in pain, have diminished e-cog status; then the chance that they respond to these drugs is minimal. I think getting these patients on the drug as soon as you have indications to do so, seems to be an appropriate thing to do.
JOSEPH: Fantastic stuff Ian. I hope our international listeners will grant me some leave for just a moment to discuss funding requirements for enzalutamide in Australia. So you need to ring the PBS authority hotline for 1 month with 2 repeats. The PBS funds enzalutamide under the following conditions: men must have castration resistant metastatic prostate cancer; it cannot be given in combination with chemotherapy; the patient must have failed treamtent with docetaxel (i.e. post chemo) OR the patient must be unsuitable for chemotherapy on the basis of a predicted intolerance to docetaxel (ie pre-chemo). Also, the patient must satisfy the following criteria which are pretty obvious- they must have an ECOG status of 2 or less, have not previously had abiraterone or develop an intolerance to abiraterone while it was still effective, and enzalutamide must be stopped on evidence of clinical or radiologic progression, ie not just PSA progression. This concept of predicted intolerance to docetaxel was discussed at the St Gallen Advanced Prostate Cancer consensus Conference in 2017 and would include men with poor renal function, poor liver function, low platelets, pre-existing neuropathy, frailty (ie ECOG 2 or more), but it may also be in men who refuse chemotherapy.
JOSEPH: That’s a lot of science to take in in one show but those papers have produced some crucial results and information for managing our prostate cancer patients so it was worth dwelling on them for a while. So the fast five facts on enzalutamide are:
IAN: 1. In men with metastatic castration resistant prostate cancer post chemo, it reduces your risk of dying by 37% and increased your life expectancy by almost 5 months.
- In these men pre-chemo, it reduces your risk of dying by 29%.
- Again, in these men pre-chemo, enzalutamide improves median progression free survival by 56% over bicalutamide,
- Enzalutamide reduces metastasis free survival in men with non-metastatic castration resistant prostate cancer by 71% over placebo.
- Beware using enza in men with a history of seizures or who are already fatigued.
JOSEPH: That’s the fast five facts. Thank you Ian for joining me.
IAN. Thanks mate. This is drug that even simple urologists like me can give.
JOSEPH: Since we recorded this, ENZAMET has been released which demonstrated a benefit for enzalutamide in the upfront newly diagnosed metastatic prostate cancer. Enzalutamide was compared to standard of care which could include docetaxel chemotherapy, and whichmay have included a first generation antiandrogen in the comparator arm such as bilcalutamide, nilutamde, or flutiamide. There was a significant improvement in overall survival at 3 years with 79% of men being alive in the enzalutamide group and 72% alive in the Standard of care only arm. Another fantastic trial form the ANZUP group and hats off to Ian Davis and the team there, as well as Chris Sweeney. So that is a wrap and thanks for listening in today. That was a real tour de force of the literature. I hope you choose to join us again next time. Please send any feedback to firstname.lastname@example.org, and to get all the latest releases, please follow us on twitter @talkingurology, or subscribe on iTunes.
You’ve been listening to Joseph Ischia, IAN and Neil Fleshner. Written by Mark Quinlan, Niall Davis, and Joseph Ischia. Produced by Joseph Ischia and Cara Webb. And a special thanks to our sponsor of this episode, Astellas, who wants everyone to be friendsa with enza.[In the background]
IAN: Oh mate, that was terrible.
JOSEPH: Just play the music.