|Ahead of print publication
The optimal upfront therapy in metastatic hormone-sensitive prostate cancer: A network meta-analysis
Hasan Mutlu1, Hakan Bozcuk2
1 Department of Oncology, School of Medicine, Istinye University, Istanbul, Turkey
2 Department of Oncology, Lara medicalpark Hospital, Antalya, Turkey
|Date of Submission||05-Jan-2020|
|Date of Decision||18-Jun-2020|
|Date of Acceptance||16-Jul-2020|
|Date of Web Publication||23-Jul-2021|
Department of Oncology, School of Medicine, Istinye University, Maltepe, Çırpıcı Yolu B Çk. No. 9, 34010 Zeytinburnu/İstanbul
Source of Support: None, Conflict of Interest: None
Background: Prostate cancer (PC) is one of the most common cancer types in men. In addition to androgen-deprivation therapy (ADT), new generation agents have provided survival advantages to patients with metastatic hormone-sensitive PC (mHSPC). In this analysis, we aimed to determine the most effective approach for treating and suppressing mHSPC using network meta-analysis (NMA).
Materials and Methods: A total of 10 trials investigating different treatment modalities were conducted using NMA. The analysis was performed for all mHSPC cases as well as for low- and high-volume and docetaxel-naive subgroups.
Results: In combination with ADT, abiraterone acetate (AA) in the general-population and high-volume-disease subgroups, and enzalutamide in docetaxel-naive and low-volume-disease subgroups have the highest probability of being the best treatment modalities in terms of overall survival. In addition, in the low-volume and docetaxel-naive settings, enzalutamide was superior to ADT (hazard ratio [HR] = 0.429, 95% CrI: 0.258–0.714 and HR = 0.533, 95% CrI: 0.375–0.756, respectively). In addition, in the high-volume and general-population settings (all trials and cases), AA was superior to ADT (HR = 1.568, 95% CrI: 1.378–1.773 and HR = 1.164, 95%CrI: 1.348–1.924, respectively).
Conclusion: The volume status based on the CHAARTED trial should be taken into account to determine an appropriate treatment strategy for mHSPC. AA plus prednisone in high-risk and high-volume-mHSPC patients and enzalutamide in low-volume-mHSPC patients could be favorable options in combination with ADT. Depending on the patient's tolerance, in high-volume mHSPC, docetaxel, or apalutamide in combination with ADT could be alternatives for AA, whereas in the low-volume mHSPC, local radiotherapy plus ADT or ADT alone could be utilized in place of enzalutamide.
Keywords: High-volume prostate cancer, hormone-sensitive prostate cancer, low-volume prostate cancer, network meta-analysis, second-generation antiandrogenes
| > Introduction|| |
Prostate cancer (PC) is the second leading cancer type in men and accounts for 29.3 new cases per 100,000 men in the world; it is also the sixth leading cause of cancer deaths in men. On diagnosis, androgen-deprivation therapy (ADT) is the gold standard in castration-naive metastatic PC (mPC). Despite the fact that no GETUG-AFU trial has ever demonstrated a survival advantage, in CHAARTED and STAMPEDE Arm-C trials, use of docetaxel plus ADT was superior to only ADT., In 2018, after docetaxel, the U. S. Food and Drug Administration also approved abiraterone acetate (AA) plus prednisone, an androgen synthesis inhibitor, in combination with ADT for upfront treatment of metastatic high-risk castration-naive PC. According to the results of the LATITUDE and STAMPEDE Arm-G trials conducted in 2019, the improvement in median overall survival (OS) was significantly improved by the addition of AA plus prednisone to ADT., Moreover, enzalutamide plus ADT was associated with significantly higher rates of OS in the ENZAMET trail; however, in the result of the interim analysis of the ARCHES trial in phase III, a comparison of enzalutamide plus ADT–an androgen-receptor inhibitor–and ADT yielded no difference in OS., In addition, in the TITAN trial, apalutamide, an androgen-receptor inhibitor of the ligand-binding domain, in combination with ADT resulted in significantly higher OS rate as compared with ADT. In two randomized trials (HORRAD and STAMPEDE Arm-H), the effectiveness of local radiotherapy was evaluated in patients with de novo metastatic hormone-sensitive PC (mHSPC) but no significant survival advantage was reported.,
Currently, in newly diagnosed mPC patients, the addition of chemotherapy, androgen-synthesis or androgen-receptor inhibitors to ADT in upfront therapy is improving the rates of OS as compared with ADT. In this study, we aimed to estimate the optimal upfront treatment using network meta-analysis (NMA) in mHSPC.
| > Materials and Methods|| |
Search strategy and selection criteria
This network analysis used summary data. Two reviewers used multiple search criteria to ensure accurate selection of clinical trials for the network analysis. We searched papers in the English language from database inception to July 15th, 2019, from PubMed, Science of Web and “Clinicaltrials.gov.” We searched books on congress proceedings from the past 3 years as well as online presentations from the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) conferences. In addition, we explored relevant web results on clinical trials. As this was the first search strategy, we took account of all randomized clinical trials (RCTs) that evaluated the use of any first-line mHSPC treatment. Furthermore, we searched relevant RCTs of additional drugs or interventions, such as docetaxel, AA, enzalutamide, apalutamide, or radiotherapy, in the first-line mHSPC treatment. In addition, we evaluated references of the selected as well as clinical studies in the relevant reviews. Finally, we conducted a Google search for any possible early press release from drug companies about the efficacy of the studied therapeutic approaches. We considered the studies satisfying the aforementioned selection criteria only if they reported OS results, as OS was the main point in this analysis. Conflicts over inclusion of trials were resolved by discussion among the authors. We followed the PRISMA NMA guidelines for this analysis.
We used the GeMTC software, which is freely available on “https://gemtc.drugis.” This software is an online tool for Bayesian NMA., Using it, researchers can upload their own dataset and perform various analyses supported by the GeMTC R package; we performed consistency models for OS analyses. The hazard ratio (HR) was the principal summary measure. Logarithmic transformation and corresponding standard errors were calculated and loaded on the database. Standard errors were calculated using previously published methods and the Comprehensive Meta Analysis Program Version 3.3.070 – November 21, 2014.,,
Along with OS, we also collected data on type of treatment received, size of trial, and year of publication. For the pairwise comparison of therapies in question, we used fixed analysis assuming a Poisson/log type of likelihood/link. For run-length parameters, 5000 was set as the number of burn-in iterations and 20,000 as the number of inference iterations.
Separate subset analyses were conducted for low- and high-volume patients. For this, relevant trials and trial arms were pooled together to conduct separate network analyses for these subgroups. Moreover, as a sensitivity test, docetaxel-naive patients were also subjected to a separate network analysis.
The funnel plots and rank probability plots were constructed to check the heterogeneity and available rank therapies, respectively. In order to assess the model's fitness, model fit statistics (residual deviance, leverage, deviance information criterion, and number of data points) were separately computed for each model.
| > Results|| |
A total of 10 clinical trials conducted on 11,087 patients were selected.,,,,,,,,, [Figure 1] shows the PRISMA flowchart for selection of the studies. All trials had published data.
The comparative effects of ADT versus ADT with first-line chemotherapy, ADT versus ADT plus radiotherapy, and ADT versus ADT plus newer hormonal agents were evaluated. The details are shown in [Table 1].
|Table 1: The properties of randomized trials included in network meta-analysis|
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First-line efficacy regarding overall survival in all hormone-sensitive disease patients
For the first-line efficacy, eight different treatment options (hormone-sensitive setting) (apalutamide + ADT, AA + prednisone + ADT, zoledronic acid + ADT, docetaxel + ADT, docetaxel + zoledronic acid + ADT, enzalutamide + ADT, radiotherapy + ADT and ADT alone) were evaluated on hormone-sensitive disease patients across all trials to determine the effect on OS. [Figure 2] shows the corresponding network graph.
|Figure 2: Network graph for all patients. Apalutamide (A), androgen-deprivation therapy, abiraterone acetate, prednisolone (P), zoledronic acid (Z), docetaxel (D), enzalutamide (E), local radiotherapy|
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In terms of OS, five treatment options consisting of apalutamide + ADT, AA + prednisone + ADT, docetaxel + ADT, docetaxel + zoledronic acid + ADT or enzalutamide + ADT was more effective than ADT alone. Notably, apalutamide + ADT, AA + prednisone + ADT, and enzalutamide + ADT did not differ in efficacy when compared with each other. However, docetaxel + ADT was less effective than AA + prednisone + ADT (HR = 1.21, 95%CrI: 1.06–1.38), and similarly, docetaxel + zoledronic acid + ADT was less effective than AA + prednisone + ADT (HR = 1.26, 95%CrI: 1.05–1.50]). Rank probability plot identified AA + prednisone + ADT as the option with the greatest probability of being the most effective treatment. [Table 2] and [Figure 3] show the details on OS-related effects of various therapeutic approaches in the first-line hormone-sensitive disease setting.
|Table 2: Comparison of the included interventions: Hazard ratio (95% confidence interval)|
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|Figure 3: Probability plot for all patients. Apalutamide (A), androgen-deprivation therapy, abiraterone acetate, prednisolone (P), zoledronic acid (Z), docetaxel (D), enzalutamide (E), local radiotherapy|
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First-line efficacy in docetaxel-naive patients
To assess the efficacy in terms of OS of various treatment options in the docetaxel naive treatment arms (recruiting patients with no concomitant docetaxel exposure), again all eight different treatment types (apalutamide + ADT, AA + prednisone + ADT, zoledronic acid + ADT, docetaxel + ADT, docetaxel + zoledronic acid + ADT, enzalutamide + ADT, radiotherapy + ADT and ADT alone) were considered. The same five treatment options consisting of apalutamide + ADT, AA + prednisone + ADT, docetaxel + ADT, docetaxel + zoledronic acid + ADT and enzalutamide + ADT were again found to be more effective than ADT alone.
Here also, apalutamide + ADT, AA + prednisone + ADT and enzalutamide + ADT did not differ in efficacy when compared with each other. However, docetaxel + ADT and docetaxel + zoledronic acid + ADT were less effective than AA + prednisone + ADT and enzalutamide + ADT. In docetaxel-naive patients, rank probability plot identified enzalutamide + ADT as the option with the greatest probability of being the best treatment. [Table 3] shows the comparison of different treatment options and [Figure 4] for the associated rank probabilities (HR = 1.21, 95%CrI: 1.06–1.38).
|Table 3: Comparison of the included interventions: hazard ratio (95% confidence interval)|
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|Figure 4: Probability plot for docetaxel-naïve patients. Apalutamide (A), androgen-deprivation therapy, abiraterone acetate, prednisolone (P), zoledronic acid (Z), docetaxel (D), enzalutamide (E), local radiotherapy|
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First-line efficacy in low-or high-volume disease patients
In patients with low-volume disease, enzalutamide + ADT was superior to docetaxel + ADT or ADT alone (HR = 0.42, 95%CrI: 0.23–0.75 and HR = 0.43, 95% CrI: 0.26–0.71). Rank probability plot identified enzalutamide + ADT as the most probable best-treatment option in this setting.
Conversely, in the high-volume-disease setting, no treatment was superior to docetaxel + ADT, and the rank probability plot identified AA + prednisone + ADT as the most probable best-treatment option for this subgroup. [Table 4] and [Table 5] and [Figure 5] and [Figure 6] show further information.
|Table 4: Comparison of the included interventions: hazard ratio (95% confidence interval)|
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|Table 5: Comparison of the included interventions: hazard ratio (95% confidence interval)|
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|Figure 5: Probability plot for patients with low-volume disease. Apalutamide (A), androgen-deprivation therapy, abiraterone acetate, prednisolone (P), zoledronic acid (Z), docetaxel (D), enzalutamide (E), local radiotherapy|
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|Figure 6: Probability plot for patients with high-volume disease. Apalutamide (A), androgen-deprivation therapy, abiraterone acetate, prednisolone (P), zoledronic acid (Z), docetaxel (d), enzalutamide (E), local radiotherapy|
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For reference to the patient groups studied (viz., all patients–docetaxel-naive patients, low-volume- and high-volume-disease patients), [Figure 7] shows the associated forest plots.
|Figure 7: Forest plots of efficacy in terms of overall survival in different patient groups (all cases–docetaxel-naïve, low-volume, and high-volume cases). Therapeutic modalities and the abbreviations are; Apalutamide (A), Androgen deprivation therapy (ADT), Abiraterone Acetate, Prednisolone (P), Zoledronic Acid (Z), Docetaxel (D), Enzalutamide (E), local radiotherapy (RT). As compared to ADT, (a-d) demonstrate hazard ratio figures of various treatment options in all patients, Docetaxel naïve patients, patients with low-volume disease, and patients with high-volume disease, respectively|
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There was no significant inconsistency in any hormone-sensitive patient's analysis with respect to the residual deviance and number of data points criteria. Furthermore, there was no inconsistency in the OS analyses. Funnel plots did not show evidence of heterogeneity.
| > Discussion|| |
PC is a common cancer type among men and one of the leading causes of cancer deaths. Because of risk reduction and toxicity, the choice of treatment combination is critical in patients with recurrent or metastasized PC. ADT approved for the adjuvant setting of PC is also primarily used in recurrent or metastatic disease in the diagnosis. Different schedules such as orchiectomy, antiandrogens, luteinizing hormone releasing hormone, agonist/antagonists, and five alpha-reductase inhibitors are offered.
Based on the results of Phase III trials reported, new agents have been added to ADT in upfront setting of HSPC, especially over the last few decades. Recently, important cancer organizations such as ASCO, ESMO, and the National Comprehensive Cancer Network (NCCN) have offered docetaxel or AA in combination with ADT to the recurrent or newly-diagnosed mHSPC patients.,, In the present analysis, some significant differences were found among different treatment regimens.
According to the results of ten analyzed trials, AA in combination with ADT demonstrated a significant OS advantage as compared with combination of docetaxel or radiotherapy with ADT, while the OS outcomes were similar between AA and second-generation anti-androgens (enzalutamide or apalutamide). In fact, this survival advantage of AA over docetaxel is opposite to the results of other analyses.,, While directly comparing docetaxel and AA in multi-arm STAMPEDE trial, Sydes et al. reported that no difference was found between AA plus ADT and docetaxel plus ADT in terms of OS. Two meta-analyses in which docetaxel and AA in mHSPC were compared indirectly have not shown any difference in terms of OS., Wallis et al. did not report any significant OS results in high-risk or metastatic hormone-naive PC. Kassem et al. did not find any OS advantage and according to the study, AA in combination with ADT had better progression-free survival results and was less toxic as compared with docetaxel in combination with ADT in NMA. By contrast, in another NMA presented in 2018, AA in combination with ADT was the most effective treatment for improving OS in patients with metastatic hormone-naive PC, and this result is consistent with our results. In another NMA performed with docetaxel plus ADT and AA plus ADT, there was only one significant survival difference in the subgroup comprising patients <70-year-old, and AA plus ADT was superior to docetaxel plus ADT in the indirect comparison in this subgroup.
Docetaxel used in diagnosis has an additive effect on survival in HSPC patients. In studies investigating the efficacy of agents other than docetaxel in NMA, standard treatment or experimental arms were found to have earlier used docetaxel in different schedule. Due to this previous docetaxel usage in combination with experimental treatment agents, the outcomes may get changed; therefore, in this present NMA, an additional analysis was performed after excluding docetaxel usage. In this new analysis, the efficacy of enzalutamide became clear.
Based on the meta-analysis reported by Vale et al., docetaxel in combination with ADT should be offered in diagnosis of mHSPC; this combination may be considered an alternative to AA, enzalutamide or apalutamide in combination with ADT in mHSPC patients. In addition, only in the LATITUDE trial, all the mHSPC patients were under high-risk as compared with ENZAMET or TITAN trials. T important inclusion criteria may tilt the treatment choice in favor of AA in high-risk mHSPC. The enzalutamide plus ADT combination may be preferable in patients with mHSPC who used docetaxel previously.
Similar to risk involved with usage of docetaxel, local disease control (radiotherapy or prostatectomy) is one of the factors affecting survival in patients with mPC. In the studies included in the present NMA, local radiotherapy or prostatectomy was performed at different ratios. Additionally, adverse effects are an important factor for consideration while choosing a treatment agent. These may affect the influence of experimental agents; therefore, the treatment should be chosen based on all of the aforementioned factors.
It was previously reported that early usage of zoledronic acid in castration sensitive or resistant setting in mPC has not provided any improvement in OS or first skeletal-related event. Moreover, the addition of zoledronic acid to docetaxel has not demonstrated any difference in OS in STAMPEDE trial. Currently, early addition of zoledronic acid to ADT may not be offered, but the studies are aiming for early addition of zoledronic acid to other agents such as AA, enzalutamide or apalutamide.
Low-volume disease in mPC has been defined as the one with < four bone lesions, no bone lesions beyond the vertebral bodies or pelvis and no visceral metastases in CHAARTED trial. Except for LATITUDE, all other trials in the present analysis have used these criteria to differentiate low-and high-volume disease. In the present analysis, STAMPEDE trials which examined docetaxel or AA were not included, as they have not reported the OS results according to volume status. In addition, because the OS outcomes for low-or high-volume subgroups were not reported in ARCHES, this study was also not included. Owing to different metastatic burden criteria than CHAARTED, HORRAD trials were also not included in the analysis. When the low-volume subgroups of other studies were compared, both enzalutamide and local radiotherapy in combination with ADT demonstrated a significant OS advantage over docetaxel in combination with ADT and ADT alone. The comparison of low-volume subgroups showed that both enzalutamide and local radiotherapy in combination with ADT have demonstrated a significant OS advantage over docetaxel in combination with ADT and ADT alone. There was no significant difference among enzalutamide, apalutamide, AA and local radiotherapy. Interestingly, in agreement with the results of their original study reports, AA and apalutamide were not superior to ADT alone. Furthermore, in combined analysis of CHAARTED and GETUG-AFU 15 trials, the patients receiving ADT alone had longer OS results in low-volume mHSPC. STAMPEDE Arm H trial which examined combination of local radiotherapy and ADT has revealed a significant longer OS result as compared with ADT alone in low-volume mHSPC patients, unlike LATITUDE, CHAARTED, GETUG-AFU 15 and TITAN trials. However, HORRAD has not shown any significant OS result in low metastatic burden PC (< five bone lesions) patients. In pooled analysis of these trials, the mHSPC patients who had < five bone metastatic lesions had a significant survival advantage with local radiotherapy in combination with ADT.
The current NCCN guidelines reported that the low-volume mHSPC patients have less benefit from combination of docetaxel and ADT in upfront treatment. In this subgroup, local radiotherapy or AA in addition to ADT or ADT alone is suggested. According to the present analysis, enzalutamide or local radiotherapy in combination with ADT may be offered as the first-line treatment option to the medically appropriate low-volume mHSPC patients. Because of having the highest probability of being the best-treatment arm for improving OS, enzalutamide plus ADT may be a preferable regimen.
We did not use STAMPEDE and ARCHES trials in analysis, as they did not report the OS results of volume-dependent subgroups. In high-volume mHSPC subgroups, AA, docetaxel or apalutamide in combination with ADT had significant OS results over ADT alone or radiotherapy plus ADT. Unlike low-volume disease, enzalutamide in combination with ADT did not provide any significant OS when compared with ADT alone or radiotherapy plus ADT. Among systemic-treatment agents in combination with ADT, we did not find any significant differences. In contrast to LATITUDE trial, TITAN trial, like CHAARTED and GETUG-AFU 15 trials which examined apalutamide, did not require high-risk mHSPC patients. Owing to high-risk population criteria that is accepted as a poor prognostic factor, AA in combination with ADT may be a preferred treatment modality in high-volume and high-risk mHSPC patients.
| > Conclusion|| |
ADT is still a cornerstone treatment for mHSPC. The addition of docetaxel or new agents to ADT improves OS results. The significantly longer OS results favor the new systemic agents that are androgen-synthesis inhibitors or second-generation anti-androgens in combination with ADT rather than docetaxel that is prevalent in current practice. According to the CHAARTED trial, in addition to risk status, the volume of metastatic disease must be determined to select treatment agents. In high-risk and high-volume mHSPC patients, AA plus prednisone in combination with ADT may be a favorable choice. Enzalutamide in combination with ADT may be a preferable treatment schedule in low-volume mHSPC patients. Local radiotherapy with ADT may be an alternative treatment modality, depending on tolerability and comorbidity in low-volume mHSPC patients. The early addition of zoledronic acid to ADT or docetaxel has not demonstrated any survival difference.
Each agent has different toxicity profile, and this is an important factor to be considered while choosing the appropriate treatment agent. The subsequent therapies after the first-line ADT combinations mentioned in the present analysis are also important to improve OS in mPC.
The choice of treatment combination is important in mHSPC. Our results suggest that treatment-schedule plan should be based on the volume status in mHSPC. Nevertheless, in further studies, head-to-head comparison of the agents is necessary to make an optimal decision.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]