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Have the days of ADT Monotherapy for Hormone Sensitive Prostate Cancer Come to an End? STAMPEDE in the June #urojc

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The much awaited results of the STAMPEDE study of abiraterone for hormone naive prostate cancer was simultataneously presented at #ASCO17 and published ‘on line ahead of print’ in the NEJM. The formal title of the study was “Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy”.

Briefly, the study randomised 1917 men with locally advanced or metastatic hormone naive prostate cancer  to receive either ADT alone or ADT in combination with abiraterone and prednisolone.  significantly higher rates of overall and failure-free survival than ADT alone.We were privileged to have the lead author Professor Nick James join us for the June #urojc.  He posted the following video which is a lovely summary about STAMPEDE.  All of us could benefit from watching this and it is a useful link for our patients.

The data from the study is clear and it was not surprising that the majority of the discussion surrounding this paper was not going to be a dissection of the methodology or dataset and its analysis but rather how these results might impact upon urological practice.

There was a somewhat provocative start to the discussion with:-

To turn the question around, we saw the following tweet:-

But @urogeek came out swinging

But he was not alone in these thoughts.

But lets be fair, these responses are from urologists immersed in clinical trials experience and highly academic centers.  The following tweet perhaps brought out what many were thinking.

But perhaps the onus is upon us to make that extra effort to learn. As has been mentioned, we manage one of the most toxic agents competently in the form of intravesical BCG for bladder cancer.

Naturally, there was bound to be some discussion about cost of treatment.

For a bit of light hearted banter, there was the following exchange which we hope nobody took too seriously.

The twitter account of the journal Prostate Cancer and Prostatic Diseases posted a poll which was responded to by 117 participants with only 10% choosing the ADT alone option.  Whilst far from scientific, does this represent a significant change in thinking?  It was not long ago where we could have predicted that almost all respondents would have chosen the ADT alone option.

And to finish up, a question answered by Nick James as follows:-

A big thanks to all who participated in the June #urojc discussion. A special thanks to lead author Nick James for his insightful comments that really added to the discussion.  We will be back for another installment of the #urojc in July.  See you then.

Henry Woo (@drhwoo) is the Director of Uro-Oncology and Professor of Robotic Cancer Surgery at the Chris O’Brien Lifehouse in Sydney, Australia. He is also Professor Surgery at the Sydney Adventist Hospital Clinical School of the University of Sydney.

 

Changing the LATITUDE of Treatment for High-Risk Hormone-Naïve Prostate Cancer: STAMPEDE-ing Towards Androgen Biosynthesis Inhibition

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zach-klaassenEarlier this month at the annual American Society of Clinical Oncology (ASCO) meeting in Chicago, IL, Dr. Karim Fizazi and Dr. Nicholas James (@Prof_Nick_James) presented results from the LATITUDE and STAMPEDE trials, respectively. These randomized controlled trials (RCTs) assessed the utility of adding abiraterone acetate (AA) + prednisone to conventional androgen deprivation therapy (ADT) among men with high-risk, hormone-naïve prostate cancer. Since Dr. Charles Huggins’ 1941 Nobel prize winning finding that ADT is highly effective in controlling metastatic prostate cancer, nearly 70 years passed before CHAARTED and STAMPEDE demonstrated in 2015 that the addition of docetaxel to ADT prolongs survival in men with high volume metastatic prostate cancer. The de novo metastatic prostate cancer global incidence is striking: 3% in the US and rising, 6% across Europe, 4-10% in Latin America, and nearly 60% in Asia-Pacific. Historically, ADT has been standard of care, however most men with metastases progress to metastatic castration-resistant prostate cancer (mCRPC) driven by the reactivation of androgen receptor (AR) signaling. The rationale for adding AA + prednisone to ADT for metastatic hormone-naïve prostate cancer patients is threefold: (i) the mechanism of resistance to ADT may develop early, (ii) ADT alone does not inhibit androgen synthesis by the adrenal glands or prostate cancer cells, and (iii) AA + prednisone improves overall survival (OS) in mCRPC patients and reduces tumor burden in high-risk, localized prostate cancer.

LATITUDE

LATITUDE was conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada. The objectives of the study were to evaluate the addition of AA + prednisone to ADT on clinical benefit in men with newly diagnosed, high-risk, metastatic hormone-naïve prostate cancer. Patients were stratified by the presence of visceral disease (yes/no) and ECOG performance status (0, 1 vs 2) and then randomized 1:1 to either ADT + AA (1000 mg daily) + prednisone (5 mg) (n=597) or ADT + placebo (n=602). The co-primary endpoints were OS and radiographic progression-free survival (rPFS). Secondary endpoints included time to: (i) pain progression, (ii) PSA progression, (iii) next symptomatic skeletal event, (iv) chemotherapy, and (v) subsequent prostate cancer therapy. The study was powered to detect an HR of 0.67 and 0.81 in favor of AA for rPFS and OS, respectively.
Over a median follow-up of 30.4 months, patients treated with ADT + AA + prednisone had a 38% risk reduction of death (HR 0.62, 95%CI 0.51-0.76) compared to ADT + placebo.

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Median OS was not yet reached in the ADT + AA + prednisone arm compared to 34.7 months in the ADT + placebo arm. OS rates at 3 years for the ADT + AA + prednisone arm was 66%, compared to 49% in the ADT + placebo arm. This OS benefit was consistently favorable across all subgroups including ECOG 0 and 1-2, visceral metastases, Gleason ≥8 disease, and bone lesions >10.

There was also 53% risk of reduction of radiographic progression or death for patients treated with ADT + AA + prednisone (median 33.0 months; HR 0.47, 95%CI 0.39-0.55) compared to ADT + placebo (14.8 months).

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Secondary endpoints showed statistically significant improvement for ADT + AA + prednisone, including time to PSA progression (HR 0.30, 95%CI 0.26-0.35), time to pain progression (HR 0.70, 95%CI 0.58-0.83), time to next symptomatic skeletal event (HR 0.70, 95%CI 0.54-0.92), time to chemotherapy (HR 0.44, 95%CI 0.35-0.56), and time to subsequent prostate cancer therapy (HR 0.42, 95%CI 0.35-0.50).

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Secondary to the results presented at ASCO, the study was discontinued after the first interim analysis. Adverse events were comparable in the two groups. Hypertension only rarely required treatment discontinuation, and only two patients discontinued treatment due to hypokalemia (no hypokalemia-related deaths). Two patients in each arm died of cerebrovascular events, and 10 patients treated with ADT + AA + prednisone compared to 6 patients treated with ADT + placebo died of cardiac disorders.

STAMPEDE

STAMPEDE is a large multi-stage, multi-arm, RCT being conducted in the United Kingdom to assess the utility of novel therapeutic agents in conjunction with ADT. Currently being tested are AA, enzalutamide, zoledronic acid, docetaxol, celecoxib and radiotherapy (RT). The AA arm of the study was presented at ASCO as a late-breaking abstract. Inclusion criteria included men with locally advanced or metastatic prostate cancer, including newly diagnosed with N1 or M1 disease, or any two of the following: stage T3/4, PSA ≥ 40 ng/mL, or Gleason score 8-10. Patients undergoing prior radical prostatectomy or RT were eligible if they had more than one of the following: PSA ≥ 4 ng/mL and PSADT < 6 months, PSA ≥ 20 ng/mL, N1, or M1 disease. Patients were then randomized 1:1 to standard of care (SOC; ADT for ≥2 years, n=957) vs SOC + AA (1000 mg) + prednisone 5 mg daily (n=960). Treatment with RT was mandated in patients with N0M0 disease, while strongly encouraged for N1M0 patients. Primary outcomes were OS and failure-free survival (FFS), where failure was defined as PSA failure, local failure, lymph node failure, distant metastases or prostate cancer death. Secondary outcome included toxicity and skeletal-related events (SREs). The study was powered to detect a 25% improvement in OS for the treatment group (requiring 267 control arm mortalities).
Both groups were balanced and patients were predominantly metastatic (52% M1, 20% N+M0, 28% N0M0), median was PSA 53 ng/mL, and 99% were treated with LHRH analogues. Over a median follow-up of 40 months, there were 262 control arm deaths, of which 82% were prostate cancer-related; there were 184 deaths in the SOC + AA + prednisone arm. There was a 37% relative improvement in overall survival (HR 0.63, 95%CI 0.52-0.76) favoring SOC + AA + prednisone.

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A Forrest plot split on stratification factors demonstrated no evidence of heterogeneity based on any of the factors, including M0/M1 status (p=0.37). Second, SOC+AA + prednisone demonstrated a 71% improvement in FFS (HR 0.29, 95%CI 0.25-0.34), with an early split in the KM curves.

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SOC + AA + prednisone also significantly decreased SREs among the entire cohort (HR 0.46, 95%CI 0.37-0.58), as well as specifically in the M1 cohort (HR 0.45, 95%CI 0.37-0.58). This resulted in a 55% reduction in SREs in the M1 subset analysis.

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When looking at treatment progression, 89% of the SOC arm went on to next line of therapy, whereas 79% of the SOC + AA + prednisone arm received additional therapy, most commonly docetaxel. As expected, the rate of Grade 3-5 adverse events was higher in the SOC + AA prednisone arm (47% vs. 33%), and were primarily cardiovascular (HTN, MI, cardiac dysrhythmias) or hepatic (transaminitis) in nature.

REACTION, INTERPRETATION & FUTURE DIRECTIONS

As has become the norm during academic conferences, there was significant buzz on Twitter over the course of the two days these results were presented:

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This also included the New England Journal of Medicine immediately tweeting after the presentations that LATITUDE and STAMPEDE were published instantaneously:

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Furthermore, immediately following Dr. Fizazi’s presentation of LATITUDE, Dr. Eric Small from @UCSF presented a discussion of LATITUDE. A number of important points were raised. First, although this was a well-designed, placebo controlled, randomized phase III study, early unblinding (although appropriate) resulting in an HR of 0.62 for OS is based on only 50% of the targeted total deaths. Making conclusions based on interim analyses must be made with caution. However, with every endpoint reaching statistical significance and conditional probability modeling, if the study had remained blinded, the probability of reaching the same conclusions is high. Second, since twice as many patients in the ADT + placebo arm received life-prolonging therapy than compared to the ADT + AA + placebo arm, the benefit of AA is not explained by more secondary life-prolonging therapy, strengthening the cause for AA + ADT.

Perhaps the most interesting and pertinent clinical comparison is assessing outcomes of the LATITUDE and CHAARTED (high-volume disease) treatment arms (AA vs docetaxel). With similar median OS outcomes between the ADT control arms of the two trials (suggesting similar populations), the HRs for OS based on treatment are nearly identical:

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Similarly, the rPFS outcomes were comparable between the two trials:

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With nearly identical OS and rPFS outcomes for men receiving ADT + AA or ADT + docetaxel, the question becomes whether the impact of adding AA to ADT is volume or risk dependent. Results from the STAMPEDE trial would suggest remarkably similar outcomes support the use of AA + ADT in patients with less burden of disease. Arguably the most important slide of the meeting was captured and tweeting by Dr. Agarwal (@neerajaiims):

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Dr. Small eloquently summarized future directions into two groups. Unanswered questions regarding efficacy include: (i) Can a genomic classifier be used to select patients more likely to benefit from AA or docetaxel? (ii) Can AA be added in even earlier settings (with radiation? Increasing PSAs?) (iii) Should AA and docetaxel be combined or used sequentially? Additionally, there are also unanswered questions regarding AA resistance, including (i) Will the mechanisms of resistance to AA be the same when used in the non-mCRPC setting? (ii) Will androgen receptor amplification still be observed? (iii) Will there be an increased risk of treatment-associated small cell/neuroendocrine prostate cancer? (iv) Does adding chemotherapy or AA to ADT result in more aggressive disease at the time of resistance? (v) What is the optimal therapy for a patient who progresses on ADT + AA, compared to a patient who progresses on ADT + docetaxel? Given the avoidance of potential chemotherapy related side effects (ie. neutropenic complications) for an oral, long-term treatment, AA + ADT should be considered standard of care for untreated, high-risk metastatic prostate cancer.

But what is the long-term economic landscape like when practice changing trials such as LATITUE and STAMPEDE suddenly thrust an expensive medication such as AA + prednisone directly to the forefront of hormone-naïve disease? Following these presentations, urologic oncologist, Twitter veteran, and Forbes correspondent Dr. Ben Davies (@daviesbj) wrote a provocative piece highlighting the potential ‘financial toxicity’ (particularly in the United States) that may result downstream of these trials:

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A conservative estimate is a wholesale cost of $115,000 per year per patient for AA + prednisone, resulting in a crude estimate of a $2.8 billion annual expenditure for the drug in the United States alone if used in the hormone-naïve setting, according to Dr. Davies. As Dr. Davies also points outs, although the patent for AA expired in 2016 and there are currently 13 applications to make generic AA, the patent for prednisone lasts until 2027, with $30 billion riding on the lawsuit. Dr. David Penson (@urogeek) succinctly summarized via Twitter:

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Strictly academically speaking, LATITUDE and STAMPEDE, in addition to the docetaxel benefits of CHAARTED, have provided clinicians with exciting Level 1 evidence for improving patient care in the high-risk/metastatic setting. The investigators and more importantly the thousands of patients and families are to be thanked and congratulated for their perseverance, hard-work, and willingness to participate in these practice-changing clinical trials. It is our job as clinicians to continue advocating the best treatment for our patients, whether this be through economic barriers in the United States, or access to appropriate care on a global scale.

 

Zach Klaassen, MD

Urologic Oncology Fellow

University of Toronto/Princess Margaret Cancer Centre

Toronto, Ontario, Canada

@zklaassen_md

 

RSM Urology Winter Meeting 2017, Northstar, California

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rsm-2017-blogThis year’s Annual RSM Urology Section Winter Meeting, hosted by Roger Kirby and Matt Bultitude, was held in Lake Tahoe, California.

A pre-conference trip to sunny Los Angeles provided a warm-up to the meeting for a group of delegates who flew out early to visit Professor Indy Gill at the Keck School of Medicine.  We were treated to a diverse range of live open, endourological and robotic surgery; highlights included a salvage RARP with extended lymph node dissection and a robotic simple prostatectomy which was presented as an alternative option for units with a robot but no/limited HoLEP expertise.

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On arrival to Northstar, Dr Stacy Loeb (NYU) officially opened the meeting by reviewing the social media urology highlights from 2016. Next up was Professor Joseph Smith (Nashville) who gave us a fascinating insight into the last 100 years of urology as seen through the Journal of Urology. Much like today, prostate cancer and BPH were areas of significant interest although, in contrast, early papers focused heavily on venereal disease, TB and the development of cystoscopy. Perhaps most interesting was a slightly hair-raising description of the management of IVC bleeding from 1927; the operating surgeon was advised to clamp as much tissue as possible, close and then return to theatre a week later in the hopes the bleeding had ceased!

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With the promise of beautifully groomed pistes and stunning views of Lake Tahoe, it was hardly surprising that the meeting was attended by a record number of trainees. One of the highlights of the trainee session was the hilarious balloon debate which saw participants trying to convince the audience of how best to manage BPH in the newly inaugurated President Trump. Although strong arguments were put forward for finasteride, sildenafil, Urolift, PVP and HoLEP, TURP ultimately won the debate. A disclaimer: this was a fictional scenario and, to the best of my knowledge, Donald Trump does not have BPH.

The meeting also provided updates on prostate, renal and bladder cancer. A standout highlight was Professor Nick James’ presentation on STAMPEDE which summarized the trial’s key results and gave us a taste of the upcoming data we can expect to see in the next few years.

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We were fortunate to be joined by prominent American faculty including Dr Trinity Bivalacqua (Johns Hopkins) and Dr Matt Cooperberg (UCSF) who provided state-of-the-art lectures on potential therapeutic targets and biomarkers in bladder and prostate cancer which promise to usher in a new era of personalized therapy.

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A personal highlight was Tuesday’s session on learning from complications. It was great to hear some very senior and experienced surgeons speaking candidly about their worst complications. As a trainee, it served as a reminder that complications are inevitable in surgery and that it is not their absence which distinguishes a good surgeon but rather the ability to manage them well.

There was also plenty for those interested in benign disease, including topical discussions on how to best provide care to an increasingly ageing population with multiple co-morbidities. This was followed by some lively point-counterpoint sessions on robot-assisted versus open renal transplantation (Ravi Barod and Tim O’Brien), Urolift vs TURP (Tom McNicholas and Matt Bultitude) and HOLEP vs prostate artery embolization for BPH (Ben Challacombe and Rick Popert). Professor Culley Carson (University of North Carolina) concluded the session with a state-of-the art lecture on testosterone replacement.

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In addition to the excellent academic programme, delegates enjoyed fantastic skiing with perfect weather and unparalleled views of the Sierra Nevada Mountains. For the more adventurous skiiers, there was also a trip to Squaw Valley, the home of the 1960 Winter Olympics. Another highlight was a Western-themed dinner on the shores of Lake Tahoe which culminated in almost all delegates trying their hand at line dancing to varying degrees of success! I have no doubt that next year’s meeting in Corvara, Italy will be equally successful and would especially encourage trainees to attend what promises to be another excellent week of skiing and urological education.

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Miss Niyati Lobo
ST3 Urology Trainee, Brighton and Sussex University Hospitals NHS Trust

@niyatilobo

 

STAMPEDE at the Dumball rally

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20160110_092926_smI’m sure I’m not the only one to board a long haul flight with the aim of catching up on a little CPD reading, only to be led astray by a series of films that later I’ll never admit to watching. Still they can be educational, as having stopped studying History at the age of 12 I’m ashamed to admit that without this educational medium I would never have been aware that the 16th President of the United States spent his formative years hunting Vampires. So in January 2016 I boarded a 10-hour flight from London to Chennai equipped with the latest publication from the STAMPEDE Study, a Workshop Manual for the Hindustan Ambassador, and a sense of inevitability that I’d be watching Matt Damon land on Mars before we’d finished crossing Kent. Taking a car manual for in-flight entertainment was not a cunning plan to encourage my neighbouring passengers to change seats before I engaged them in conversation. I have an unread copy of Donald Trump’s 2009 tome “Think Like a Champion” that fulfils that role perfectly. The manual was my homework, as I was en route to join the Dumball Rally.

The Dumball Rally is a fancy-dress charity banger rally – that raises money for the Teenage Cancer Trust. Since its inception in 2006 (Amsterdam to Athens) it has raised over £650,000. This year the route was Chennai to Goa, via Kanyakumari (the Southern Tip of India), the Western Ghats, Cochin, and for our team a stapes-shuddering Rock Bar in Mysore. 37 Hindustan Ambassadors awaited us on the start-line, their fully enclosed monocoque chassis based on the Morris Oxford Series III that last rolled off the production line in Cowley in 1959 – just in case you’re thinking I didn’t read the manual.

As a Clinical Oncologist I’m admit to being in one of the more geek-orientated specialities. Who needs a PDE5-inhibitor when a graph depicting a Bragg Peak excites you? So as I read about the history of Hindustan Motors, and the inner workings of my Ambassador, I was struck by the commonality of their significant anniversaries with those of my chosen profession. Hindustan Motors was founded in 1942, the year after Charles Huggins published his seminal paper on Prostate Cancer. The Morris Oxford Series III began production in 1956, the same year that Hertz and Li first described the successful use of cytotoxic chemotherapy (methotrexate) to treat a solid tumour (Choriocarcinoma). The production of the Hindustan Ambassador began in 1958, the year Rosalind Franklin died. The final version of the Ambassador (the Avigo) began production in 2004, the same year Tak327 was published demonstrating a survival advantage for Docetaxel and prednisone in metastatic castrate-resistant prostate cancer. Who said altitude and wine don’t mix well?

The rally began on 10th January 2016. Our team, dressed as Dick Dastardly and Muttley (wise outfit choices in greater than 30 degrees centigrade heat), were pitted against a range of other themed cars from a fire-engine (with wired-in power washer), a yellow-submarine (broadcasting “Beatles” songs), to the Jungle Book (which continuously grew with foliage collected from the roadside). The Rally results are summarised below, and compared with the results from the STAMPEDE Study (finally read on the return flight).

STAMPEDE is a study assessing the impact of intensifying initial treatment for locally advanced and metastatic prostate cancer. Its novel Multi-Arm Multi-Stage (MAMS) design may prove as important to future cancer care as the results generated by the study itself. Basically MAMs permits multiple different primary questions to be addressed simultaneously and sequentially over a far shorter time period, and with fewer subjects, than would be required to address the questions separately.

Median Overall Survival for the Standard of Care (SOC) arm of STAMPEDE was 71 months, which increased to 81 months with the addition of 6 cycles of Docetaxel Chemotherapy. There was no additional benefit with the use of Zoledronic acid (with or without Docetaxel). Looking at the subset with metastatic disease, Median Overall Survival increased from 45 months to 60 months with the addition of Docetaxel, demonstrating that this should now be standard of care in suitable patients with metastatic disease. Regarding the Median Overall Survival for the Dumball Rally, there were insufficient events (only 1 car had to be abandoned), and follow-up is too short (8 days) to report meaningful data.

Median Failure Free Survival (FFS) for the SOC arm of STAMPEDE was 20 months, which increased to 37 months with Docetaxel. The hazard ratios were similar for both metastatic and non-metastatic subsets. Again there was no additional benefit with the addition of Zolendronic acid. The median FFS for the Hindustan Ambassador was about 6 hours. The passenger seat and seat-belt broke in our car whilst exiting the car-park having just collected it; most cars over-heated daily (interestingly the electrics are located directly beneath the radiator overflow); one engine seized completely; and an axel broke on Dumball 1, the organiser’s car.

Grade 3 + adverse events reported within the first 6 months of the STAMPEDE Study increased from 17% in the SOC arm to 36% with the addition of Docetaxel. Despite this the chemotherapy was well tolerated, with most patients completing all 6 planned cycles with minimal changes in dose or scheduling. Regarding the Rally, ironically it coincided with India’s National Road Safety Week. Their slogan “Hurry leads to worry; Accident brings tears; Safety brings cheers” repeated Orwellian-style in my subconscious as we negotiated the Indian traffic. In India they drive on the left……and sometimes the right, the middle of the road, the pavement –in fact wherever they want! A gentle toot of the horn lets other road users know where they are, and it appears to be the driver’s responsibility to avoid anything in front of them – no matter how late it pulls out. But it works – and everything keeps moving with good humour and smiles. It wasn’t unusual to be horrendously cut-up, only for the “offending driver” to then stop, get out the car and come over for a friendly chat and a photo opportunity. As a result, there were minimal adverse events – other than putting on a few additional Kg in weight eating curry 3 times a day.

Work on next year’s Dumball Rally has already started – rumours are that it may involve Nepal. If anyone is interested in taking part, please look at their website: www.dumball.org

 

Simon Hughes is a Consultant Clinical Oncologist at Guy’s and St Thomas’, London

 

 

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