Dr Renu Eapen is a Consultant Urologist in the Genitourinary Oncology service at the Austin Hospital Olivia Newton-John Cancer Centre and the Peter MacCallum Cancer Centre. Dr Eapen undertook research in Female Pelvic Medicine and Reconstructive Surgery at University of Texas Southwestern Dallas. She went on to complete a subspecialty Fellowship at the University of Toronto, Canada and subsequently obtained her robotics and uro-oncology Fellowship at University of California, San Francisco. She is currently undertaking her PhD at the University of Melbourne. Axel Merseburger is Professor of Urology and Chairman of the Department of Urology at University Hospital Schleswig‑Holstein, Campus Lübeck, in Lübeck, Germany. He was appointed Associate Professor, in 2009, and Professor, in 2012, at Hannover Medical School. He is Principal Investigator for multiple phase 2 and phase 3 clinical trials. Prof. Merseburger is as an advisor for the European Association of Urology (EAU) Guidelines Group for Renal Cancer, and has previously served as Chairman of the EAU Guidelines Group for Lasers and Technologies. Prof. Merseburger acts as a reviewer and editorial board member for several urology and oncology indexed journals, is Associate Editor of the World Journal of Urology, and is Editor-in-Chief of European Oncology & Haematology.
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Talking Urology podcast transcript
So You’re Gonna start a patient on ADT
JOSEPH ISCHIA: Hi everybody and welcome. I’m Joseph Ischia and today we’re continuing our new podcast series with the team at Talking Urology where we are bringing the literature to life. Today’s podcast is … So You’re Gonna….. ‘start a patient on ADT’. This sounds like a simple topic, but there’s more to starting a man on ADT than copying the name on that pen you have from the 90s. Get ready for the deepest dive on ADT you ever wanted to take. Today I’m joined by my special co-host Renu Eapen a Urologist from the Austin and Peter Macallum Hospitals in Melbourne but Renu, welcome.
RENU EAPEN: Thank you so much for having me today Joseph. As you said I’m a urologist at the Austin and Peter Mac in Melbourne. I’m also a PhD candidate at the University of Melbourne, we’re doing some exciting research at Peter Mac in particular, looking at the role of lutetium PSMA in treating high risk prostate cancer.
JOSEPH: Now that’s fascinating because a lot of those men are going to end up needing ADT. So we’ll also be joined by international thrash metal guitarist Axel Rose…..sorry just seeing If you’re still paying attention. Our guest is international ADT expert Axel Merseburger!
AXEL MERSEBURGER: My name is Axel Merseburger, I am a urologist and Chairman of the Department of Urology at Lubeck in Germany. Thank you for inviting me to speak on ADT.
JOSEPH: As usual we have an exciting podcast for you which we will go through once we get back from thanking our sponsor.
Sponsor Advert: “We would like to thank our sponsor Ipsen for providing an independent educational grant. Ipsen had no influence on the editorial contents. “
JOSEPH: Welcome back and let’s get started by mentioning the two names that always come up in the first paragraph of any discussion on ADT, Huggins and Hodges, or to their mothers, Charles Brenton Huggins and Clarence Hodges. Let’s go back to the year 1941….a time when World War 2 was dominating world affairs, Citizen Kane premiered in the USA and these 2 enthusiastic young physicians began to investigate the effects of androgen deprivation therapy on prostate cancer. That last one isn’t remembered as widely, but we’re onto it today.
RENU: They began to investigate the effects ADT by surgical castration or by suppressing luteinizing hormone-releasing hormone (LHRH) production at the level of the hypothalamus with diethylstilbestrol (DES). Their findings on suppression were revolutionary as surgical and pharmacologic castration resulted in dramatic palliation of painful bony metastases and an unprecedented improvement in quality of life in men with advanced prostate cancer.
JOSEPH: Now listeners……Members involved in this era of medical research are frequently referred to as ‘ The Greatest Generation’ of researchers and the accomplishments of Huggins and Hodges were globally recognised in 1967 when both were awarded a Noble Prize for their pioneering work in prostate cancer….for some reason I haven’t been enlisted as a member of ‘The Greatest Generation’ yet, but I’m sure my invite is in the post, it must be because I moved recently …
RENU: I think you’ll be waiting a long time, Joseph! Now…back to the Greatest Generation……Investigations into the beneficial clinical effects of ADT continued at a rapid rate during the 1970s. In 1971, Andrew Schally and his buddies purified the decapeptide gonadotropin-releasing hormone, also referred to as LHRH and found that chronic exposure to LHRH suppressed testosterone by desensitizing pituitary cells through downregulation of the LHRH receptors. This golden generation of researchers were truly ahead of their time!
JOSEPH: The first randomised clinical trial of ADT found that a monthly depot of the LHRH agonist leuprolide was equivalent to 3mg of Diethylstillbestrol (DES) in reducing serum testosterone to castrate levels and was published in the NEJM in 1984. The same year that Michael Jackson released the highest selling album of all time, Thriller. Now, the main advantage of leuprolide over diethylstillbestrol was a lower incidence of cardiovascular toxicity. Prevention of this adverse event meant that leuprolide ultimately replaced DES and orchiectomy as the preferred approach to androgen deprivation.
RENU: Over the next 30 years, urologists and scientists tinkered around with different ADT formulae by substituting the sixth amino acid position on leuprolide to develop the agents goserelin, triptorelin, and histrelin, all of which are still commercially available as LHRH agonists today. Let’s recap the five recognised indications for ADT:
- Symptomatic metastatic prostate cancer.
- Neoadjuvant ADT with radiation to the prostate.
- Biochemical (PSA) recurrence after prior curative treatment.
- Palliation in co-morbid men with locally advanced disease.
- Asymptomatic metastatic prostate cancer.
JOSEPH: Bang, 5. Got it. Those top two are pretty clear cut and there will always be some discussion around what PSA you start it in the biochemical recurrence state after surgery or radiation, or in a palliative setting. One interesting point is whether we need to continue ADT in the advanced castration resistant prostate cancer setting. Let’s hear from Axel what he thinks.
AXEL: Doctors are well aware of mode of action of ADT on GnRH agonists and antagonists, and I think they use it well. However, there was some discussion on stopping in the later stage of the disease when it comes to castration resistant prostate cancer. There is only 1 trial prospectively looking at this, whether or not you could stop ADT in MCRPC, this is a small 60 patient phase 2 trial published by Carsten Ohlmann, a German colleague of mine working in Bonn now, who just showed the data final analysis at ASCO in Chicago couple of weeks ago. It showed that in this situation in the heavily pre-treated patients, it probably makes no difference when using Abiraterone if you use concomitant ADT or not. However, this is a very small study and all the pivotal trials, all the trials that are published, it doesn’t matter if it’s Radium-223, Abi or Enza; all were with ADT. When looking at an even earlier setting, we have approvals in some countries for M0 CRPC. So non-evidence of disease, rising PSA, ADT for a while and then rising PSA again with a fast doubling time – we have the approval of Apalutamide and Enzalutamide showing that the metastasis free survival is prolonged for up to 2 years in this setting when using those novel hormone treatment. This again underlines the need of ADT and the more intensified ADT especially when it comes to metastatic disease. This has shown also at the last ASCO with the release of the TITAN data which was simultaneously published in the New England Journal of Medicine, Kim Chi has shown the data, randomised phase 3 trial comparing just classical ADT in primary metastatic prostate cancer or metastatic regardless of high volume or low volume, compared to ADT in combination with Apalutamide. This resulted in 33% prolongation of overall survival and remarkable PFS benefit with a hazard ratio of 0.48. This again justifies the use of ADT, especially in metastatic prostate cancer.
JOSEPH: Ok Renu, let’s move on. Why is 50 ng/dl set as the level we consider adequate castration?
RENU: Simple really, bilateral orchidectomy is considered the reference standard for ADT as it lowers serum testosterone level well below 50 ng/dl in <12 hours. Although it is a simple and cost-effective procedure, it is non-reversible and, as you can all imagine, carries significant psychological burden in some patients.
JOSEPH: Ok some men want the drugs. As we know, LHRH agonists are associated with a temporary rise in testosterone, that can lead to temporal clinical flare with worsening signs and symptoms of the disease. However, the LHRH antagonists competitively bind to pituitary LHRH receptors, rapidly reducing luteinising hormone and testosterone levels without an initial testosterone flare. Importantly, all the ADT agents have similar side effect profiles and a similar ability to lower serum testosterone to castrate levels. The LHRH antagonist claims to have some reduced cardiovascular toxicity but we will await the prospective clinical trials to see if this bears out. Alright Renu, So you have started the man on ADT, what are the big early side effects to warn patients about?
RENU: The big three are: hot flashes, loss of libido, and erectile dysfunction.
1. 60-80% of men will experience significant hot flashes that can be effectively treated with hormonal agents: in one RCT by Irani in the Lancet Oncology in 2010, venlafaxine (selective serotonin re-uptake inhibitor, 75 mg), cyproterone acetate (100 mg) and medroxyprogesterone (20 mg) all demonstrated improvements within 1 month.
2. 58-100% will suffer from a loss of libido.
3. And the overwhelming majority of men taking LHRH agonists will develop erectile dysfunction.
JOSEPH: Those are … not great. 100%, that’s a big number, but still 10% less than the effort I demand my kids put in when competing in their Saturday morning sport. Let’s take a look at the more chronic adverse events now, which can be conveniently also be divided in to three 3 categories: musculoskeletal, haematological, and cardiovascular events….
- Firstly musculoskeletal…..the bones!!..…The prevalence of osteopenia and osteoporosis are high in patients newly diagnosed with prostate cancer (40%). Within the first year of ADT, absolute BMD loss is ≈5% as demonstrated in a study by EJ Hamilton in 2010 in the Journal of Clinical Epidemiology and Metabolism. If bone mineral density significantly decreases, treatment with bisphosphonates are recommended. Weekly oral alendronate appears to be enough to maintain BMD in non-metastatic population
- Secondly haematological…..the blood stream!!…..Men with advanced prostate cancer are predisposed to developing anaemia due to haematuria from locally advanced prostate cancer and due to bone marrow infiltration by metastatic disease. Testosterone increases production of erythrogenesis-stimulating proteins. Therefore, LHRH agonists may cause or exacerbate anemia by indirectly inhibiting erythrogenesis.
- And thirdly….or finally….cardiovascular….the heart!! In 2006…. Keating reported increased cardiovascular morbidity and mortality associated with LHRH agonists in the Journal of Clinical Oncology (JCO). The increased cardiovascular toxicity was hypothesized to be mediated through changes in lipoproteins, arterial stiffness, and QT interval prolongation.
RENU: Joseph let’s ask Axel, what side effect of ADT do you think we are particularly bad at monitoring for or looking after as urologists starting ADT? What concerns him the most about starting ADT?
AXEL: What concerns me the most is we have on the one hand localised prostate cancer – the big discussion on erectile function and as you know – all the stuff with the robot some advertising the erectile function would even get better when have radical prostatectomy. We have a lot of discussion on quality of life –men’s health and then once it comes to rising PSA or metastatic disease, we give ADT and this makes hot flushes, decreases libido, this basically kills all erections. I think here the patient information needs to be improved and a well-educated patient… only like a well-informed patient should get ADT and has to agree with the side effects. It has to be consulted in the pros and cons of ADT. So I think in regards to metastatic disease comes the most the underuse of bone protecting agents. Since we all know the modern substances and also ADT supports the development of osteoporosis. So I really think, especially when seeing Bertrand Tombal data, first look inside a phase 3 trial published at ASCO where it showed the safety of the combination of Enzalutamide and Radium-223, showing when you combine this with modern bone protecting agents like Zoledronic Acid or Denosumab, that you can basically erase skeletal related events. And we are not doing this, this will rise up to 33%.
JOSEPH: So Axel has touched on the adverse events we see with ADT. Next we thought we’d ask him, what is his opinion on stereotactic radiation for delaying the onset of ADT and its associated adverse events?
AXEL: In very small trials in mostly retrospective series it has been shown and we’ve also worked on this topic that ADT can be delayed in about 50% of patients in those – I have to say very small series – for about 2 years. However, when looking at the most robust evidence we have from the STAMPEDE trial, when looking at the data published by Chris Barker LANCET 2018, this is like the evidence for treating oligometastatic disease. Again all patients had ADT and about 18% of the patients even received Docetaxel in the setting concomitant or prior to the radiation. So I think especially in metastatic disease, this has to be a dual but not a triple therapy with the new data we have now with ENZAMET and Titan published in ASCO a couple of weeks ago.
RENU: Great work Joseph and Axel. Let’s talk intermittent ADT. Intermittent ADT can be effective in reducing the morbidity of ADT treatment. Encouragingly, for patients concerned about their sex lives —
JOSEPH: Which I’m guessing is approaching 100%.
RENU: Yes, for them, studies (for example Higano 1996, Malone 2005) have demonstrated the return of potency and resolution of anaemia with an intermittent ADT regimen. In addition, a meta-analysis by Tsai in 2013 demonstrated similar overall and cancer-specific survival, whilst possibly reducing the side-effects, such as sexual dysfunction and hot flushes, with improvements to quality of life (QoL) and physical activity….. However, I do think that it is important to emphasise that patients who clearly do not benefit oncologically from intermittent ADT are patients with symptomatic high-burden disease and high initial PSA levels.
JOSEPH: Good point Renu! And those who want more on this topic can listen in to a fantastic podcast called Talking Urology where we chatted to David Quinn about the SWOG intermittent vs continuous ADT trial.
RENU: They still talk about that episode in the laurels of podcasting history.
JOSEPH: Too right I do.
RENU: Let’s pivot to discussing maximum androgen blockade. The theory is that 90-95% of androgens are produced by the testes and 5-10% by the adrenals or the cancer itself. Therefore, maximum androgen blockade snuffs out the testes and then antagonises any of the testosterone that may still be floating around. The impact of the adrenal androgens on prostate cancer in men with LHRH agonists is debatable but our famous researcher Mr. Huggins did demonstrate a clinical benefit of surgical adrenalectomy in men with disease recurrence after orchiectomy… now Joseph how can we achieve maximum androgen blockade?
JOSEPH: Adrenalectomy? There is nothing this guy didn’t think of back in the 40’s! You know I have a bronze statue of him in my atrium.
RENU: Wow, so much to unpack there. You have an atrium?
JOSEPH: Sitting room? Nave? I don’t know what would you call it? Anyway, MAB can be achieved pharmacologically by combining an LHRH agonist with an antiandrogen. The first generation antiandrogens are flutamide, bicalutamide, and nilutamide which block the effects of adrenal androgens at the androgen receptor. Interestingly, 3 early randomized studies have demonstrated the advantage of initiating MAB at the time of diagnosis for metastatic prostate cancer. The mean increase in overall survival attributable to MAB demonstrated in these studies was approximately 7 months*. The important names and journals to remember on the benefits of MAB are Crawford NEJM 1989, Jankneat J Urol 1993 and Dijkman J Urol 1997. I asked Axel, what does he think is the current role of maximal androgen blockade?
AXEL: We have had maximum androgen blockage for years with a combination of bicalutamide. This has changed about 5 years ago when we saw the data with early use of Abiraterone, it made sense to start early and not to perform maximum androgen blockage, but rather start early especially in metastatic disease with a novel hormone treatment. Following ASCO, with what you just mentioned, ENZAMET and TITAN data, we have somehow maximum androgen blockage 3.0, something like a revival of this setting. So this is really something new again, but not with the use of Bicalutamide. So in metastatic disease you would probably want to start according to LATITUDE and STAMPEDE either with Abiraterone in combination with ADT or Docetaxel. Now days when we’ve seen the data on Apalutamide in TITAN, once it’s approved. However, I think it is just in metastatic disease. However, in non-metastatic disease in private urology practices; still there is use of Bicalutamide and in some patients with very long PSA doubling time, it may be justified, yes.
JOSEPH: We asked Axel, Is there any role for withdrawing Bicalutamide with the progression of castration resistance or should we just move quickly onto the next agent?
AXEL: This is very historic. I think this was one of the first publications I worked on 20 years ago on a book chapter on withdrawal of anti-androgen and the evidence is sparse there. It has never shown an overall survival benefit. In case of metastatic disease, I would urge the colleagues to intensify treatment, to use modern concepts in the treatment of metastatic prostate cancer.
RENU: Now I think it’s time we got stuck into the juicy stuff… The next thing that really interests me is the Messing trial where there was a large survival advantage for starting ADT early in people with positive lymph nodes. It’s not something that I know anybody who does regularly. Let’s see what Axel thinks. Does he think the Messing trial still has a role, or has PSA testing and newer imaging techniques really superseded any need for early ADT in these patients?
AXEL: So Messing trial. It still has a role even though it was published years ago. I think it is good evidence we have in this clinical situation, and we have new evidence just shown at the ASCO that half a year of ADT concomitant to radiotherapy in the salvage situation prolongs progression free survival. Not yet overall survival and we had the Shipley data a couple of years ago with Bicalutamide for 2 years 150mg every day in the situation when radiation was performed in the salvage and the PSA rise setting, so here we have evidence in using just ADT when it comes to PSA rise, when it comes to local recurrence mostly with a combination with radiotherapy. However, this counts more for lymphatic diseases, it counts more for primary very small disease volume, non detectable with conventional imaging.
RENU: Ok listeners, I’m going to change direction a little here.
JOSEPH: Bold move, especially for a guest host.
RENU: Hey, you only live once! So, there has been an explosion in the literature over the last 5-10 years on newer androgen receptor pathway targeted therapies.
JOSEPH: Alright, let’s begin by saying that these are very effective agents. Discussing where they fit in to the prostate cancer journey is a podcast or two in itself, but let’s group them together for today. We have abiraterone acetate which is an oral cyp 17 inhibitor which prevents extragonadal and testicular androgen synthesis; there is also enzalutamide which is a super potent androgen receptor antagonist (please listen to our podcast on enzalutamide), and the newer agents, Apalutamide and the currently in clinical trials, darolutmaide. Let’s go big picture here: as of recording this podcast, Abi and enza & app are effective post and pre-chemo in castration resistant prostate cancer. Enza and apa are effective in non-metastatic castration resistant prostate cancer, and abi, apa, and enza are all effective upfront in the newly diagnosed metastatic hormone naïve prostate cancer. So it seems that maximum androgen blockade is back and more maximal than ever! Now each of these drugs has its own quirks and cautions, and we hope we can cover these in another podcast.
RENU: Well we are approaching the end of another podcast but we’ve arguably left of the most important and clinically relevant part of ADT till last …….how to monitor and follow-up patients on ADT? I’ve heard a lot of opinions from a lot of urologists on this subject, and everyone seems to vary with their follow-up protocol. Joseph, a penny for your thoughts on this?
JOSEPH: You’ve probably over paid there Renu but I can tell you I do follow the EAU guidelines and I’ll try to summarise them in the following 5 points:
- Measure PSA and testosterone levels one month after starting ADT to assess PSA response and whether testosterone reaches castrate levels.
- PSA level every 3 to 6 months to monitor for disease progression and to determine whether castrate resistance status develops.
- Also check haemoglobin and creatinine for anaemia and renal failure either from disease or from adverse effects of drugs.
- DEXA scan in men at high risk of developing osteoporosis before androgen ablation.
- Haemoglobin A1c, fasting glucose, lipid profile, and blood pressure at baseline and every three months to monitor for metabolic syndrome, diabetes, and hypercholesterolaemia.
- Last but not least, a high-five for staying on the follow-up plan.
JOSEPH continued: This podcast has been a thunderbolt of information on everything you need to know about ADT. To summarise, here are the 6 fast facts from this ADT podcast that we have covered over the last 20 minutes or so…
- Huggins and Hodges were globally recognised in 1967 when both were awarded a Noble Prize for their pioneering work in ADT and advanced prostate cancer.
- Acute adverse events include hot flashes, loss of libido, and erectile dysfunction.
- Chronic adverse events are classified as musculoskeletal, haematological, and cardiovascular events.
- In patients with metastatic disease, ADT is efficacious with a mean expected response duration of ≈3 years.
- I have an atrium in my home.
- There is level 1 evidence demonstrating that abiraterone acetate and enzalutamide as well as the newer agents apalutamide and darolutamide are going to be associated with improved overall survival compared to placebo and bicalutamide respectively.
RENU: And I think that’s a wrap on ADT for the moment. Hopefully, you’ve learned a thing or two about starting and monitoring patients on ADT and thanks again for listening. And thanks to Axel Merseberger who has shared his invaluable expertise and insights with us today.
JOSEPH: And thanks to you as well Renu. It’s been a pleasure! Now I just want to give a shout out to a podcast that you are doing with Declan Murphy. What is it about and how can we access it?
RENU: Thanks Joseph! That’s right, Declan Murphy and I have launched GUcast from our studio at Peter Macallum Cancer Centre. So it’s a podcast series where we love talking about all things GU, we really focus on genitourinary cancers but we’re open to all urological topics really. Recently we’ve been taking with our colleagues around the world to see how they’re coping n the COVID pandemic and it’s really been fascinating to hear what the great minds think about how we should managing GU cancers during this time. So please check us out, you can search for GUcast on Spotify, Applecast, Pocketcast or your favourite podcast platform, subscribe to us, drop us a like or as ever, we’d love to hear your feedback
JOSEPH: You can now get all our podcasts on iTunes, apple podcasts, or on twitter @talking_urology. Remember to send all feedback to firstname.lastname@example.org
You’ve been listening to Joseph Ischia, Renu Eapen and Axel Merseberger. Written by Niall Davis, Mark Quinlan and Joseph Ischia. Produced by Joseph Ischia and Cara Webb.
So You’re Gonna, the practical urology podcast for those who love urology, proudly brought to you by Ipsen.