Metastatic Burden in Hormone-Naive Prostate Cancer: A Tale of Two Subgroups

Abstract

Since 2013, the sequential results of eight pivotal trials have heralded substantial changes to therapy for men with newly diagnosed metastatic prostate cancer. Patients previously treated with androgen deprivation therapy (ADT) as monotherapy are now benefitting from additional therapies, including primary site radiotherapy and chemo-hormonal and androgen receptor-targeted systemic treatments. Notwithstanding this success, debate continues over the optimal first-line agent relating to disease characteristics and to the sequencing of subsequent treatments at progression. Part of this debate includes the question of which therapeutic combination should be used for individuals and, in particular, whether decisions about specific treatments should be based on stratification by metastatic burden at initial presentation. In this editorial, we revisit the issues surrounding treatment allocation based on disease burden and review the recently published data addressing this topic. Docetaxel was the first therapy used in combination with ADT to be evaluated in metastatic hormone-naive prostate cancer (mHNPC). Three randomised controlled trials, GETUG-AFU-15, CHAARTED and STAMPEDE, addressed this issue and the updated data from these trials have been published and ultimately combined in a full meta-analysis, the ‘STOPCAP’ programme [1Gravis G. Boher J.M. Joly F. Soulie M. Albiges L. Priou F. et al.Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial.Eur Urol. 2016; 70: 256-262Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar, 2Kyriakopoulos C.E. Chen Y.H. Carducci M.A. Liu G. Jarrard D.F. Hahn N.M. et al.Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial.J Clin Oncol. 2018; 36: 1080-1087Crossref PubMed Scopus (293) Google Scholar, 3Clarke N.W. Ali A. Ingleby F.C. Hoyle A. Amos C.L. Attard G. et al.Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer long-term survival results from the STAMPEDE trial.Ann Oncol. 2019; https://doi.org/10.1093/annonc/mdz396Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 4Tierney J.F. Vale C.L. Parelukar W.R. Rydzewska L. Halabi S. Evidence synthesis to accelerate and improve the evaluation of therapies for metastatic hormone-sensitive prostate cancer.Eur Urol Focus. 2019; 5: 137-143Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. The GETUG-AFU-15 trial, which randomised 385 patients to ADT ±9 cycles of docetaxel, did not show a significant overall survival benefit. The CHAARTED trial, which randomised 790 patients, reported a significant overall survival benefit with docetaxel + ADT over ADT alone. However, in a subgroup analysis by metastatic burden, patients with ‘high volume’ disease defined as either visceral metastases and/or four or more bone metastases with at least one outside the vertebral bodies and/or pelvis, had greater benefit and it was concluded that patients with ‘low volume’ disease should not receive the ADT/docetaxel combination (Table 1). The STAMPEDE ‘docetaxel comparison’ randomised high-risk M0 and M1 patients. The authors reported significant improvement in overall survival but did not show heterogeneity of treatment effect, concluding that the ADT/docetaxel combination was effective without stratification for volume/burden. In light of this uncertainty, some treatment guidelines recommended that docetaxel should be considered only for patients with a high metastatic ‘volume’, whereas in others, treatment was recommended irrespective of ‘volume/burden’ [[12]National comprehensive cancer network clinical practice guidelines in oncology - prostate cancer version 2. 2019https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdfGoogle Scholar,[13]European association of urology guidelines: prostate cancer. 2016https://uroweb.org/wp-content/uploads/EAU-Guidelines-Prostate-Cancer-2016.pdfGoogle Scholar]. Subsequent analysis of data from STAMPEDE, applying CHAARTED volume-based criteria to the overall trial cohort, showed that up to 40% of men who presented with ‘low burden’ mHNPC as defined by CHAARTED would be ineligible for combination treatment with ADT + docetaxel.Table 1Summary of overall survival hazard ratios in low and high burden/risk subgroups in metastatic hormone-naive prostate cancer phase III randomised controlled trials*Study [reference]Control groupComparator groupLow burden/riskHR (95%CI)High burden/riskHR (95%CI)% de novo M1GETUG-AFU-15 [[1]Gravis G. Boher J.M. Joly F. Soulie M. Albiges L. Priou F. et al.Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial.Eur Urol. 2016; 70: 256-262Abstract Full Text Full Text PDF PubMed Scopus (239) Google Scholar]ADTADT + docetaxel1.02 (0.67–1.55)0.78 (0.56–1.09)72%CHAARTED [[2]Kyriakopoulos C.E. Chen Y.H. Carducci M.A. Liu G. Jarrard D.F. Hahn N.M. et al.Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial.J Clin Oncol. 2018; 36: 1080-1087Crossref PubMed Scopus (293) Google Scholar]ADTADT + docetaxel1.04 (0.70–1.55)0.63 (0.50–0.79)73%STAMPEDE arm C comparison [[3]Clarke N.W. Ali A. Ingleby F.C. Hoyle A. Amos C.L. Attard G. et al.Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer long-term survival results from the STAMPEDE trial.Ann Oncol. 2019; https://doi.org/10.1093/annonc/mdz396Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]ADTADT + docetaxel0.76 (0.54–1.07)0.81 (0.64–1.02)95 %LATITUDE [[5]Fizazi K. Tran N. Fein L. Matsubara N. Rodriguez-Antolin A. Alekseev B.Y. et al.Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial.Lancet Oncol. 2019; 20: 686-700Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar]ADT + placeboADT + abiraterone acetate and prednisoneNA0.66 (0.56–0.78)100%STAMPEDE arm G comparison [[6]Hoyle A.P. Ali A. James N.D. Cook A. Parker C.C. de Bono J.S. et al.Abiraterone in “high-” and “low-risk” metastatic hormone-sensitive prostate cancer.Eur Urol. 2019; 76: 719-728https://doi.org/10.1016/j.eururo.2019.08.006Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]ADTADT + abiraterone acetate and prednisolone0.66 (0.44–0.98)0.54 (0.41–0.70)95%HORRAD [[7]Boevé L.M.S. Hulshof M. Vis A.N. Zwinderman A.H. Twisk J.W.R. Witjes W.P.J. et al.Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD trial.Eur Urol. 2018; 75: 410-418https://doi.org/10.1016/j.eururo.2018.09.008Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar]ADTADT + prostate radiotherapy0.68 (0.42–1.10)1.06 (0.80–1.39)100%STAMPEDE arm H comparison [[8]Parker C.C. James N.D. Brawley C.D. Clarke N.W. Hoyle A.P. Ali A. et al.Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.Lancet. 2018; 392: 2353-2366Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar]ADT (±docetaxel)ADT + prostate radiotherapy (±docetaxel)0.68 (0.52–0.90)1.07 (0.90–1.28)100%ENZAMET [[9]Davis I.D. Martin A.J. Stockler M.R. Begbie S. Chi K.N. Chowdhury S. et al.Enzalutamide with standard first-line therapy in metastatic prostate cancer.N Engl J Med. 2019; 381: 121-131Crossref PubMed Scopus (365) Google Scholar]ADT + NSAA (±docetaxel)ADT + enzalutamide (±docetaxel)0.43 (0.26–0.72)0.80 (0.59–1.07)58%TITAN [[10]Chi K.N. Agarwal N. Bjartell A. Chung B.H. Pereira de Santana Gomes A.J. Given R. et al.Apalutamide for metastatic, castration-sensitive prostate cancer.N Engl J Med. 2019; 381: 13-24Crossref PubMed Scopus (336) Google Scholar]ADT + placeboADT + apalutamide0.67 (0.34–1.32)0.68 (0.50–0.92)84%HR, hazard ratio; CI, confidence interval; ADT, androgen deprivation therapy; NSAA, non-steroidal antiandrogen.*The ARCHES trial also evaluated ADT ± enzalutamide, but overall survival data were immature at the last follow-up [[11]Armstrong A.J. Szmulewitz R.Z. Petrylak D.P. Holzbeierlein J. Villers A. Azad A. et al.ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer.J Clin Oncol. 2019; 37: 2974-2986Crossref PubMed Scopus (208) Google Scholar]. Therefore, it was not included in the table. Open table in a new tab HR, hazard ratio; CI, confidence interval; ADT, androgen deprivation therapy; NSAA, non-steroidal antiandrogen. *The ARCHES trial also evaluated ADT ± enzalutamide, but overall survival data were immature at the last follow-up [[11]Armstrong A.J. Szmulewitz R.Z. Petrylak D.P. Holzbeierlein J. Villers A. Azad A. et al.ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer.J Clin Oncol. 2019; 37: 2974-2986Crossref PubMed Scopus (208) Google Scholar]. Therefore, it was not included in the table. In 2019, the STAMPEDE docetaxel comparison reported long-term follow-up results of 1086 M1 patients (724 control/362 docetaxel) stratified by metastatic burden according to CHAARTED [[3]Clarke N.W. Ali A. Ingleby F.C. Hoyle A. Amos C.L. Attard G. et al.Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer long-term survival results from the STAMPEDE trial.Ann Oncol. 2019; https://doi.org/10.1093/annonc/mdz396Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar]. At a median follow-up of 78.2 months, overall survival was improved significantly for patients receiving ADT +docetaxel over ADT alone (HR 0.81, 95% CI 0.69–0.95) regardless of metastatic burden (interaction P value = 0.827). Importantly, in the low metastatic burden subgroup, 5-year survival was better in patients treated with ADT+ docetaxel than in “high volume” and the benefit of combination treatment was seen across all outcome measures including metastasis free and prostate cancer specific survival. The reason for the differing conclusions of STAMPEDE, GETUG-AFU-15 and CHAARTED may relate to statistical interpretation and variation in post-primary treatment therapies but one key variance may lie in the nature of the different trial cohorts recruited. Most patients in STAMPEDE had de novo metastatic disease (~95%). By comparison, nearly 25% of the patients enrolled in the CHAARTED and GETUG-AFU-15 trials had metastatic prostate cancer that had developed following radical local treatment of their primary. This category of disease has a different natural history compared with de novo metastatic disease [[14]Finianos A. Gupta K. Clark B. Simmens S.J. Aragon-Ching J.B. Characterization of differences between prostate cancer patients presenting with de novo versus primary progressive metastatic disease.Clin Genitourin Cancer. 2018; 16: 85-89https://doi.org/10.1016/j.clgc.2017.08.006Abstract Full Text Full Text PDF Scopus (15) Google Scholar]. The low volume groups in CHAARTED and GETUG-AFU-15 trials also had insufficient patient numbers in ‘low volume’ de novo patients for definitive comment: there were only 154 such patients in CHAARTED compared with 362 in STAMPEDE. This larger number of patients in STAMPEDE provides stronger evidence for the validity of the subgroup findings and this in turn provides greater confidence for clinicians to consider docetaxel chemotherapy as first-line treatment for all such patients, regardless of metastatic burden. The second area of uncertainty relates to the licensing indication and treatment guidelines for abiraterone acetate in mHNPC, which are linked to ‘disease risk’. The LATITUDE trial enrolled patients with ‘high-risk’ disease, defined arbitrarily as having two or more of the following: ≥3 bone metastases on bone scan, Gleason score ≥8 and any visceral metastases [[15]Fizazi K. Tran N. Fein L. Matsubara N. Rodriguez-Antolin A. Alekseev B.Y. et al.Abiraterone plus prednisolone in metastatic, castration-sensitive prostate cancer.N Engl J Med. 2017; 377: 352-360Crossref PubMed Scopus (936) Google Scholar]. The results from this registration trial showed a significant improvement in overall survival with continuous ADT + abiraterone acetate and prednisone at the trial's second interim analysis at 36 months. The findings formed the basis for international licencing of the drug's combination use in this setting. Currently, ADT + abiraterone acetate and prednisone is licensed only for high-risk mHNPC as defined in LATITUDE. The STAMPEDE trial's abiraterone comparison randomised a broader population encompassing high-risk M0 and M1 patients. A pre-planned subgroup analysis of 901 M1 patients treated within the abiraterone comparison reported at the 48-month time point. It showed overall benefit in all patients presenting with metastases, with no heterogeneity of effect, suggesting that ‘risk’ categorisation was not relevant to benefit from treatment in these patients [[16]James N.D. de bono J.S. Spears M.R. Clarke N.W. Mason M.D. Dearnaley D.P. et al.Abiraterone for prostate cancer not previously treated with hormone therapy.N Engl J Med. 2017; 377: 338-351Crossref PubMed Scopus (800) Google Scholar]. In a subsequent post-hoc analysis of STAMPEDE data, sub-categorising M1 patients using both LATITUDE ‘risk’ and CHAARTED ‘volume’ criteria the issue of risk and volume was investigated further [[6]Hoyle A.P. Ali A. James N.D. Cook A. Parker C.C. de Bono J.S. et al.Abiraterone in “high-” and “low-risk” metastatic hormone-sensitive prostate cancer.Eur Urol. 2019; 76: 719-728https://doi.org/10.1016/j.eururo.2019.08.006Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. This study reported unequivocally that all primary and secondary outcome measures in this aspect of the STAMPEDE trial were associated with a survival benefit in both low- and high-risk subgroups treated with ADT + abiraterone acetate and prednisolone, whether using LATITUDE risk or CHAARTED volume methodology for patient sub-stratification. It was also noted that a large proportion of patients were classified as either low risk (LATITUDE) ~47% or low volume (CHAARTED) ~44%. Thus, if stratification based on these criteria was used, a large proportion of the patient population, who would otherwise qualify for this combination, would be ineligible based on the existing licensing recommendations. Irrespective of volume or risk criteria ADT + abiraterone acetate and prednisone/prednisolone is effective as a systemic therapy for all patients. A further disease burden effect has been reported in relation to the use of radiotherapy to the primary prostate site in men presenting with de novo metastatic disease. In May 2018, the HORRAD trial reported on 432 patients with mHNPC randomised to ADT ± prostate radiotherapy [[7]Boevé L.M.S. Hulshof M. Vis A.N. Zwinderman A.H. Twisk J.W.R. Witjes W.P.J. et al.Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD trial.Eur Urol. 2018; 75: 410-418https://doi.org/10.1016/j.eururo.2018.09.008Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar]. The trial was negative overall, but a subgroup analysis suggested that there may be survival benefit in a subgroup of patients with fewer than five bone metastases (HR 0.68, 95% CI 0.42–1.10). However, the trial, and in particular, its subgroup, was too small to reach a robust conclusion. The ‘M1|RT’ comparison in STAMPEDE was much larger, randomising >2060 patients, thereby enabling a pre-planned and properly powered overall and subgroup analysis. This was subsequently undertaken and reported in 2018. The hypothesis ultimately tested was that in a pre-specified subgroup analysed by metastatic burden there would be benefit in patients with a low metastatic burden as defined by CHAARTED criteria (staged with standard Tc scintigraphic bone scan and conventional computed tomography/magnetic resonance-based cross-sectional imaging). The STAMPEDE M1|RT comparison showed that overall, taking the general population of de novo presenting M1 prostate cancer patients, primary site radiotherapy was ineffective. However, the pre-planned directionally hypothesised subgroup analysis by metastatic burden as defined by CHAARTED criteria showed that standard imaging was predictive of improved overall survival benefit in patients presenting with low metastatic ‘volume’. In this subgroup of 819 patients with de novo mHNPC, 3-year overall survival was 81% in those having standard of care (SOC) + radiotherapy compared with 73% using SOC alone [[8]Parker C.C. James N.D. Brawley C.D. Clarke N.W. Hoyle A.P. Ali A. et al.Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial.Lancet. 2018; 392: 2353-2366Abstract Full Text Full Text PDF PubMed Scopus (437) Google Scholar]. These results have changed practice internationally and prostate radiotherapy with systemic therapy is now recommended as a first-line treatment for patients with newly diagnosed low burden mHNPC in international guidelines. A further recent exploratory analysis of the STAMPEDE ‘M1|RT’ comparison has now shown a threshold effect based on bone metastasis counts and actual metastasis volume as measured using validated bone scan volume measuring tools [[17]Ali A. Hoyle A. Parker C. James N. Brawley C. Parmar M. et al.Evaluating the predictive role of automated bone scan index in selecting newly diagnosed metastatic prostate cancer patients for prostate radiotherapy: a STAMPEDE trial exploratory analysis.Eur Urol Suppl. 2019; 18: e1852-e1853https://doi.org/10.1016/S1569-9056(19)31343-0Abstract Full Text PDF Google Scholar,[18]Ali S.A. Hoyle A. James N.D. Parker C. Brawley C. Attard G. et al.Benefit of prostate radiotherapy for patients with lymph node only or < 4 bone metastasis and no visceral metastases: exploratory analyses of metastatic site and number in the STAMPEDE “M1|RT comparison”.Ann Oncol. 2019; 30: v330https://doi.org/10.1093/annonc/mdz248.007Abstract Full Text PDF Google Scholar]. An improvement in failure-free survival (FFS) and overall survival was noted in patients with only non-regional lymph nodes or fewer than four bone metastases on bone scan, irrespective of location [[18]Ali S.A. Hoyle A. James N.D. Parker C. Brawley C. Attard G. et al.Benefit of prostate radiotherapy for patients with lymph node only or < 4 bone metastasis and no visceral metastases: exploratory analyses of metastatic site and number in the STAMPEDE “M1|RT comparison”.Ann Oncol. 2019; 30: v330https://doi.org/10.1093/annonc/mdz248.007Abstract Full Text PDF Google Scholar], thus redefining the volume thresholds for treatment in this setting. A number of limitations remain regarding current definitions of metastatic disease burden. None acknowledge the presence of metastatic lymph nodes and using the CHAARTED classification for low volume an unlimited number of metastases may be present when they are confined only to the axial skeleton or lymph nodes. Given our current understanding of the association of increasing metastatic burden with worsening prognosis, this results in misclassification and therefore suboptimal treatment of a significant number of patients. Using LATITUDE risk criteria, the Gleason score is known to be confounded by sampling bias associated with different biopsy techniques. Moreover, some visceral disease behaves in a more indolent manner (e.g. lung versus liver), whereas other collective case studies suggest certain metastatic site combinations are associated with a poorer prognosis, e.g. bone and non-regional lymph nodes [[19]Ali A. Hoyle A. Mistry H. Clarke N.W. Importance of non-regional lymph nodes in assigning risk in primary metastatic prostate cancer.BJU Int. 2019; 123: 65-73Crossref PubMed Scopus (6) Google Scholar]. Similarly, large volume, bulky lymph node-only metastases can be associated with a different prognosis. Finally, overall survival rates differ depending on initial disease presentation; metachronous metastatic disease is associated with better survival compared with low and high volume presenting de novo. Temporal changes in imaging methodology will probably be influential in the future. Existing metastatic burden definitions have been defined using conventional imaging with computed tomography, magnetic resonance imaging and technetium 99 bone scans. The increasing use of more sensitive imaging modalities, including68 Ga prostate specific membrane antigen (PSMA) positron emission tomography (PET) and whole-body magnetic resonance imaging, will have an impact, which will probably influence and may potentially redefine metastatic burden. The corollary of this is the consequent impact on treatment decisions in individual patients, which will inevitably be altered by the advent of these newer and potentially more sensitive detection methods if clinicians take the newer findings at face-value. It is important to recognise that these newer imaging modalities are currently not validated in their prediction of natural history of disease, their role in prognostication and, perhaps more importantly, their prediction of response to treatment. An appreciation of the different biology underlying metachronous and de novo disease is also important, in addition to considering the anatomical location of the primary metastatic site and the combination of differing sites and organ systems affected. This consideration is crucial to understanding and stratifying the natural history of disease on an individual basis. It is also fundamentally important to recognise this when considering new data emerging from case series and future randomised trials. Ongoing studies within the STAMPEDE and other trials, combined with collaborative initiatives such as the STOPCAP and ICECaP programmes, continue to refine our existing definitions of metastatic distribution by incorporating such factors as metastatic lymph node burden to optimise treatment selection. We hope that this will improve our understanding of natural history and treatment-related outcomes by combining high-quality data in more robust, larger scale datasets, thereby enabling better decision making in first-line treatment and treatment sequencing. This may ultimately give the clinical community many more ‘subgroups’, but if such future conclusions are based on solid foundations both clinicians and patients will be better placed. On review of the current available evidence all newly diagnosed men with mHNPC should be considered for all systemic therapies irrespective of metastatic burden, whereas only those with low burden disease should receive prostate radiotherapy. The authors declare no conflict of interest. Guarantor of integrity of the entire study: NWC. Study concepts and design: N/A. Literature research: AMH, AA, NWC. Clinical studies: N/A. Experimental studies/data analysis: N/A. Statistical analysis: N/A. Manuscript preparation: AMH, AA, NWC. Manuscript editing: AMH, AA, NWC.