Tag Archive for: CHAARTED


Article of the week: External validation of the prostascore model in metastatic hormone‐sensitive PCa patients recruited to the CHAARTED study

Every Week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

External validation of the prostascore model in patients with metastatic hormone‐sensitive prostate cancer recruited to the CHAARTED study

Omar Abdel‐Rahman* and Winson Y. Cheung†

*Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; †Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada



To externally validate ‘prostascore’ in patients with metastatic hormone‐sensitive prostate cancer recruited to the phase III CHAARTED study.


We conducted a retrospective analysis of the prospectively collected data from patients with metastatic hormone‐sensitive prostate cancer in the CHAARTED study, a phase III multicentre study conducted between 2006 and 2014. The main outcome of the present analysis was overall survival, assessed using Kaplan–Meier analysis or log‐rank testing, in the whole cohort according to different prostascores. In addition, patients with different scores were compared according to treatment arm.

Fig 1. Kaplan-Meier curves for (A) overall survival according to Prostascore.


A total of 702 cases had complete baseline data, allowing calculation of prostascores and inclusion in the present analysis. Overall survival was assessed according to prostascores in the entire cohort and the P value for overall survival trend was significant (P < 0.001). Likewise, progression‐free survival was assessed according to prostascores in the entire cohort and the P value for progression‐free survival trend was also significant (P < 0.001). Overall survival comparisons according to treatment arm were evaluated among different prostascores. Notably, the P value for overall survival difference was not significant for a prostascore = 2 (P = 0.702), but was significant for scores of 3, 4 and 5 (P < 0.05). The cause‐specific hazard ratio for cancer‐specific survival (adjusted for treatment arm used) was also evaluated. The P value for pairwise comparisons between different scores was significant (P < 0.01) except for the comparison between scores 4 and 5.


The present study further confirms the role of prostascore in predicting the outcomes of patients with metastatic hormone‐sensitive prostate cancer and also highlights its potential role in therapeutic decision‐making.

Editorial: Prognostic and predictive models in hormone-sensitive PCa

The article by Abdel‐Rahmen and Cheung [1] in the current issue of BJUI takes the Prostascore model [2] developed from epidemiological Surveillance, Epidemiology and End Results (SEER) data and applies it to the prospective randomised trial data from the ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) [3]. This sort of modelling is invaluable, given the inevitable limitations of epidemiological data (retrospective, no data cleaning, key items such as performance status missing, etc.). For models to be useful, they need to be able to discern prognostic categories reliably and with sufficient difference in outcome that they can usefully contribute to clinical decision‐making. They also need to perform better than existing oncological models, such as TNM stage, as outcome predictors. To be truly useful, they also need to identify subgroups of patients who may differentially benefit from different treatments (e.g. human epidermal growth factor receptor 2 [HER2] status in breast cancer therapy with trastuzumab). It is thus important to differentiate prognostic models (which predict outcome but do not help select treatment) from predictive models (which predict outcome and also help select who may benefit from treatment). A common mistake in this setting is to assume that patients with worse outcomes may benefit from more aggressive treatment, whilst those with better outcomes may require less treatment. This is a frequent confounding bias in retrospective data such as SEER. The key test is to look at good‐ and poor‐prognosis patients and examine whether the benefit from (say) chemotherapy is proportionately the same or different in both groups. If the proportional benefit is the same, the model is purely prognostic, if the proportional benefit is different (e.g., a bigger benefit in worse patients), the model is, in addition, predictive. A randomised trial such as CHAARTED is thus ideal for separating these two factors. It is also worth noting that just because a model predicts a relatively better outcome in one subgroup vs another, it does not mean that all patients do not benefit. For example, programmed death 1 (PD‐1) pathway molecule staining is generally prognostic in advanced bladder cancer and partly predictive of better response to PD‐1 pathway drugs such as atezolizumab [4] and pembrolizumab [5], but all patients derive benefit and hence PD‐1 pathway staining is not useful in selecting for treatment.

How does the Prostascore model fare against these various tests? As a prognostic model it clearly separates patients into groups with plausible differences in outcome. However, there exist many systems already that do this and in the clinic, these are probably not useful – it is well understood that men with extensive disease and visceral metastases will do worse than those with less disease – treatment for all will include androgen‐deprivation therapy (ADT). More recently, trial data have emerged showing survival benefit from the first‐line addition of either docetaxel [3, 6] or abiraterone [7, 8] to ADT. There is controversy about whether this benefit is confined to men with high‐volume disease as claimed by some [9], or applies more generally, as per Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) [6] and the Systemic Treatment Options for Cancer of the Prostate (STOpCaP) meta‐analysis [10]. Can Prostascore help to resolve this problem? Sadly the answer is no. The analysis presented here [1] does not offer convincing evidence of a useful predictive value with respect to selection for first‐line docetaxel. Firstly, the sample size is small (702 men), with only 118 in the lowest risk category (who of course also have the lowest event rate, hence proportionately even less power). In the higher‐risk categories, there seems to be clear evidence of benefit from docetaxel (larger numbers of men and higher event rates). No pooled analysis is presented, but it seems likely that this would show a benefit from docetaxel in the whole sample set, exactly as reported in CHAARTED [3]. Data from underpowered, post hoc, subgroup analysis should not be over‐interpreted [11].

How should we move forward from here? The STAMPEDE group will be presenting data from both the docetaxel and abiraterone parts of the study, classified both by the high‐/low‐volume split in CHAARTED [3] and the high‐/low‐risk split in the LATITUDE trial (multinational, randomised placebo‐controlled phase III clinical trial of men with newly diagnosed, high‐risk metastatic prostate cancer who had not previously received ADT. All patients had at least two of three risk factors: Gleason score of ≥8, ≥3 bone metastases, or ≥3 visceral metastases) [7]. If evidence of a differential response to these agents by these prognostic tools exists, it may be worth applying the Prostascore tool to the STAMPEDE dataset. If there is no evidence of these existing prognostic classifiers also being predictive of best therapy choice, there is probably only a limited role for Prostascore as a prognostic tool in an already crowded space. risk factors and risk of developing cancer.

Nicholas D. James

Institute of Cancer and Genomic Sciences, University of Birmingham,
Queen Elizabeth Hospital, Birmingham, UK

  1. Abdel‐Rahman O, Cheung WY. External validation of the prostascore model in patients with metastatic hormone‐sensitive prostate cancer recruited to the CHAARTED study. BJU Int 2018; 122: 394–400
  2. Abdel‐Rahman O. Prostascore: a simplified tool for predicting outcomes among patients with treatment‐naive advanced prostate cancer. Clin Oncol (R Coll Radiol) 2017; 29: 732–8
  3. Sweeney CJ, Chen YH, Carducci M et al. Chemohormonal therapy in metastatic hormone‐sensitive prostate cancer. N Engl J Med 2015; 373: 737–46
  4. Balar AV, Galsky MD, Rosenberg JE et al. Atezolizumab as first‐line treatment in cisplatin‐ineligible patients with locally advanced and metastatic urothelial carcinoma: a single‐arm, multicentre, phase 2 trial. Lancet 2017; 389: 67–76
  5.  Bellmunt J, de Wit R, Vaughn DJ et al. Pembrolizumab as second‐line therapy for advanced urothelial carcinoma. N Engl J Med 2017; 376: 1015–26
  6. James ND, Sydes MR, Clarke NW et al. Addition of docetaxel, zoledronic acid, or both to first‐line long‐term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016; 387: 1163–77
  7. Fizazi K, Tran N, Fein L et al. Abiraterone plus prednisone in metastatic, castration‐sensitive prostate cancer. N Engl J Med 2017; 377: 352–60
  8. James ND, de Bono JS, Spears MR et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 2017; 377: 338–51
  9. Gravis G, Boher JM, Chen YH et al. Burden of metastatic castrate naive prostate cancer patients, to identify men more likely to benefit from early docetaxel: further analyses of CHAARTED and GETUG‐AFU15 Studies. Eur Urol 2018; 73: 847–55
  10. 10 Vale CL, Burdett S, Rydzewska LH et al. Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone‐sensitive prostate cancer: a systematic review and meta‐analyses of aggregate data. Lancet Oncol 2016; 17: 243–56
  11. Spears MR, James ND, Sydes MR. Thursday’s child has far to go’ – interpreting subgroups and the STAMPEDE trial. Ann Oncol 2017; 28: 2327–30


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

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 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.


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).


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).


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 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.


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.


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.


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.


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:


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


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:


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


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):


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:


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:


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



Sailing into “UnCHAARTED” waters

Chemotherapy comes alive for prostate cancer!

staff-chowdhury1Systemic therapy for metastatic prostate cancer has radically changed in the last 10 years with the introduction of several novel agents that have shown significant improvements in progression free and overall survival. These have all been studied in metastatic castrate refractory prostate cancer (mCRPC) and have improved overall survival but in each case by less than 6 months. (The latest major breakthrough is the introduction of a relatively old drug, docetaxel chemotherapy, earlier in the disease for hormone sensitive patients).

In this week’s New England Journal of Medicine we see the eagerly awaited results from the CHAARTED study from Christopher Sweeney and colleagues. This novel study aimed to improve treatment for men with newly diagnosed hormone sensitive metastatic prostate cancer by adding docetaxel chemotherapy to androgen deprivation therapy (ADT).

790 men with newly diagnosed metastatic prostate cancer were randomised to ADT plus docetaxel (6 cycles at 75mg/m2) or ADT alone. The addition of docetaxel to ADT was shown to significantly improve overall survival by 13.6 months (57.6 months vs. 44.0 months; p<0.001). The clinical benefit was greatest in the subgroup with high volume disease where the improvement in overall survival was 17 months (49.2 months versus 32.2 months). High volume disease was defined as the presence of visceral metastases and/or 4 or more bone metastases with at least one beyond the vertebral bodies or pelvis. The combination was well tolerated with approximately 6% of patients having neutropenic fever and one death possibly related to docetaxel.

The results from this study are truly practice changing. Supporting evidence from the UK STAMPEDE study (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) was presented at this year’s American Society of Clinical Oncology (ASCO) meeting. STAMPEDE showed that for men with metastatic hormone sensitive prostate cancer 6 cycles of docetaxel in addition to ADT improved median overall survival by 22 months (43 versus 65 months).

Chemotherapy for metastatic prostate cancer has had a checkered past with a lack of enthusiasm and nihilism from clinicians and patients. The results from CHAARTED and STAMPEDE are already changing those views. The prostate cancer community needs to react to these results and look to make this treatment available to all suitable men. There are issues with regards to costs of chemotherapy (although docetaxel is now generic), workload, sequence, patient selection, toxicity management, etc. The CHAARTED and STAMPEDE investigators must also use this opportunity to interrogate the tumour samples from these studies to see if they can identify biomarkers that predict docetaxel activity. We will not get this opportunity again as docetaxel + ADT will be be standard of care for future studies.

The clinical benefit from the addition of docetaxel to ADT is one of the largest seen in any oncology study. All men presenting with newly diagnosed metastatic prostate cancer should be considered for 6 cycles of docetaxel in addition to ADT.


Simon Chowdhury is a Consultant Medical Oncologist at Guy’s, King’s and St Thomas’ Hospitals, London. He is actively involved in clinical trial research into urological cancers.



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