Hormoongevoelig gemetastaseerd prostaatkanker wordt gekenmerkt door uitgezaaide

ziekte die kan worden geremd door hormoondeprivatietherapie (ADT)  hetzij medicamenteus, hetzij middels subcapsulaire orchidectomie, waardoor de serumtestosteronspiegels verlaagd worden tot castratieniveau. Staat strikt genomen buiten beschouwing van deze module, maar ihkv kostenbesparing en minder bijwerkingen lijkt er een grotere plaats voor de orchidectomie, met wel als nadeel een narcose / operatie. Het definitieve karakter is juist een pre. Sinds 2015 worden geselecteerde patiënten bovendien behandeld met chemotherapie of een androgeenreceptorsignaleringsremmer (ARSI). Onlangs zijn combinaties van androgeendeprivatietherapie (ADT) en verschillende ARSI's, chemotherapie of bestralingstherapie toegevoegd als behandelingsstrategie. Deze module gaat over de volgende behandelstrategieën:

• nieuwe middelen in deze setting in combinatie met ADT, namelijk: abirateron, enzalutamide en apalutamide;
• nieuwe behandeling in combinatie met ADT, namelijk uitwendige radiotherapie;
• reeds bekende chemotherapiebehandeling in combinatie met ADT, namelijk docetaxel.

In deze module wordt onderscheid gemaakt tussen hoog volume en laag volume ziekte. Hoog volume ziekte wordt gedefinieerd als (≥ 4 botmetastasen inclusie ≥ 1 buiten wervelkolom of bekken of viscerale metastasen). Laag volume ziekte betreft gemetastaseerde ziekte dat niet aan de criteria van hoog volume voldoet.

What are the effects of ADT combined with an ARSI or chemotherapy or radiation compared to ADT alone in patients with newly diagnosed hormone-sensitive metastatic prostate cancer?

1. ADT plus Docetaxel vs. ADT only

2. ADT plus Abirateron versus ADT only

3. ADT plus Apalutamide vs. ADT only

4. ADT plus Enzalutamide vs ADT only

5. ADT plus radiotherapy of the prostate vs. ADT only

Description of studies

A total of 10 RCTs were included in the literature analysis. The main characteristics of these RCTs are presented in Table 1. Further details are included in the evidence table (see tab ‘Verantwoording’).

Table 1. Overview of the included trials.

¹ Data from Cornford 2021

² Data from Burdett 2019

High volume versus low volume hormone sensitive metastatic prostate cancer

For the subgroup analysis by volume (high versus low), Wang 2020 used a total of 8 out of 10 trials. The ARCHES (Armstrong 2019 reported data cutoff on October 14, 2018 after a median follow-up time of 14.4 months). and STAMPEDE-G arm could not be included because relevant outcome data was missing. As in the CHAARTED study, Wang 2020 defined high-volume disease as the presence of visceral metastases or ≥4 bone lesions with ≥1 lesion beyond the vertebral bodies and pelvis on CT and Bonescan.

The LATITUDE study used no strict volume criteria, but risk criteria: at least two of the three high-risk prognostic factors (Gleason score of ≥8, presence of three or more lesions on bone scan, or presence of measurable visceral metastasis except lymph node metastasis on CT). The LATITUDE study contributed only to the subgroup high risk.

Results

1. ADT plus Docetaxel versus ADT alone

In the three large Docetaxel RCTs, patients in the experimental group received Docetaxel (75 mg/m2 every three weeks, within 3 months of ADT initiation), with or without the addition of prednisone or prednisolone, for a number of up to six (Sweeney, 2015 and James , 2016) or nine cycles (Gravis, 2016). Most patients started Docetaxel-ADT therapy within one month of randomization.

The data in Table 2 is from Wang 2020 and Sathianathen 2018 unless otherwise noted.

Table 2. Results ADT plus docetaxel versus ADT alone, three trials (STAMPEDE C-arm, Clarke 2019; GETUG-AFU-15, Gravis 2016 and CHAARTED, Sweeney 2015).

CI = confidence interval

NA = not available

¹ The certainty of the evidence has been lowered by one level due to study limitations (possible performance bias) (Sathianathen 2018) and the confidence interval also encompasses the boundary for clinical decision-making, but we decided not to further downgrade for this.

² The certainty of the evidence has been lowered by one level due to study limitations (possible performance and detection bias) (Sathianathen 2018).

³ The certainty of the evidence has been lowered by two levels due to study limitations, imprecision (data is from 1 trial and sample size < 2000) and additional concerns about selective reporting (outcome only adequately reported by one of three trials) (Sathianathen 2018).

⁴ The certainty of the evidence has been lowered by two levels due to severe study limitations (possible performance bias, detection bias and attrition bias).

The subgroup analysis was considered relatively convincing and showed an interaction between the volume of the disease and the magnitude of effect. The survival advantage of ADT plus Docetaxel versus ADT alone is probably clinically relevant for the high-volume subgroup, but not for the low-volume subgroup.

The absolute effects relative to ADT only treatment for men with hormone sensitive metastatic prostate cancer, not taking the volume of the disease into account, are:

• Treatment with ADT plus Docetaxel is likely to result in 94 fewer deaths per 1000 men (95% CI 51 to 137 fewer deaths) after 5 years (Sathianathen 2018).
• The HR of 0.78 translates into an absolute and clinically relevant improvement in 4-year survival of 9% (95% CI: 5 to 14 months) (Cornford, 2021).
• ADT plus Docetaxel likely leads to 159 fewer patients with disease progression per 1000 men (95% CI 202 to 116 fewer) after 5 years (Sathianathen 2018).
• In the three studies, toxicity was predominantly haematological, with approximately 12-15% grade 3-4 neutropenia and 6-12% grade 3-4 febrile neutropenia. Addition of Docetaxel may increase the incidence of grade III to V adverse events compared to ADT alone. The estimated absolute effect is 405 more adverse events of grade III to V per 1000 men (95% CI 243 to 621 more events) after a median follow-up of 50 months (Sathianathen 2018).
• ADT plus Docetaxel probably results in little or no difference in quality of life at 12 months compared to ADT alone (Sathianathen 2018).

2. ADT plus Abiraterone plus Prednisolone vs. ADT alone

In the RCTs examining Abiraterone, patients in the experimental group received abiraterone acetate (1000 mg/day) with prednisone at a dose of 5 mg/day (Fizazi, 2017) or prednisolone 5 mg/day (James, 2017). Abiraterone-ADT treatment until radiologic, clinical, or PSA progression. The data in Table 3 are from Sathianathen 2020.

The subgroup analysis of the ‘low volume disease’ is based on the STAMPEDE G-arm trial, as the LATITUDE trial only included high risk patients.

Table 3. Results ADT plus Abiraterone plus Prednisolone versus ADT alone, two trials (STAMPEDE G-arm, James 2020 and LATITUDE, Fizazi 2019)

NA = not available

* Data for this subgroup analysis based on the STAMPEDE G-arm trial only.

¹ The confidence interval just encompasses the boundary for clinical decision-making (0.7), but we did not downgrade for this.

² The certainty of the evidence has been lowered by two levels due to serious imprecision (data is from 1 trial and sample size < 2000).

³ The certainty of the evidence has been lowered by one level due to study limitations (Sathianathen 2020).

⁴ The certainty of the evidence has been lowered by two levels due to study limitations (possible attrition bias) (Sathianathen 2020) and imprecision (data is from 1 trial and sample size < 2000).

The survival advantage of ADT plus Abiraterone plus Prednisolone versus ADT alone is clinically relevant. The subgroup analysis was not considered convincing and did not show a clear interaction between the volume of the disease and the magnitude of effect.

The absolute effects relative to ADT only treatment for men with hormone sensitive metastatic prostate cancer, are:

• The survival benefit of ADT plus Abiraterone corresponds to 163 fewer deaths (210 fewer to 115 fewer) per 1000 men after five years (Sathianathen 2020).
• ADT plus Abiraterone likely leads to 369 fewer (456 fewer to 256 fewer) cases of disease progression per 1000 men after a median follow-up of 30 months (Sathianathen 2020).
• The increased risk of complications/side effects corresponds to 162 more (105 more to 224 more) grade III to V adverse events per 1000 men after a median follow-up of 30 months (Sathianathen 2020).
• ADT plus Abiraterone is likely to result in little or no difference in quality of life at 12 months compared to ADT alone (as measured by the Functional Assessment of Cancer Therapy Prostate Total Score (FACT-P) range 0 to 156; higher values indicate better quality of life life) (Sathianathen 2020).

3. ADT plus Apalutamide vs. ADT alone

In the TITAN trial, the intervention group received ADT plus Apalutamide (240 mg daily) and the control group received ADT plus placebo. The data in table 4 is from Chi 2021, unless stated otherwise.

Table 4. Results ADT plus Apalutamide versus ADT alone, one multinational trial (TITAN, Chi 2021).

¹ The certainty of the evidence has been lowered by one level due to study limitations (possible performance bias) (Chi 2021). The confidence interval also encompasses the boundary for clinical decision-making, but we decided not to further downgrade for this.

² In addition, apalutamide plus ADT resulted in the lowest risk (relative to ADT plus Docetaxel, Abiraterone or Enzalutamide, for overall complications and adverse events, anemia and hypertension (SUCRA: 28, 25, and 24%, respectively) (Chen, 2020).

³ The certainty of the evidence has been reduced by two levels due to serious imprecision (data is from 1 trial and sample size < 2000).

The survival advantage of ADT plus Apalutamide over ADT alone is clinically relevant. The subgroup analysis was not considered convincing and did not show a clear interaction between the volume of the disease and the magnitude of effect.

4. ADT plus Enzalutamide vs ADT alone

In the ENZAMET trial, the addition of Enzalutamide to ADT was compared with standard non-steroidal anti-androgen therapy plus ADT. Testosterone suppression was started up to 12 weeks before randomization.

The final results of the ARCHES trial relevant to this guideline module were not yet available in May 2021. The early results (14.4 months median follow-up) from this study showed that radiographic disease progression and death was lower in the ADT plus enzalutamide group than in the ADT plus placebo group and 63% had high volume disease (Virgo 2021). The planned end date of the ARCHES trial is December 2023.

The data in Table 5 are based on the ENZAMET trial (Davis 2019), unless stated otherwise.

Table 5. Results ADT plus Enzalutamide versus ADT alone, one trial (ENZAMET; Davis 2019).

NA = not available

* We noticed in Wang 2020 another effect estimate then reported in the original article by Davis 2019. We assume that the effect estimate of Davis 2019 is correct.

¹ The certainty of the evidence has been lowered by one level due to imprecision as the confidence interval encompasses the boundary for clinical decision-making (and data is from 1 trial).

² The certainty of the evidence has been lowered by two levels due to study limitations and serious imprecision (data is from 1 trial and sample size < 2000).

³ Grade III-V adverse events: 321/563 in intervention group and 241/558 in control group.

⁴ Data from the ARCHES trial (Stenzl 2020), measured at 73 weeks follow-up.

The subgroup analysis might show an interaction between the volume of the disease and the magnitude of effect, but evidence was low certainty and this was considered as not convincing for separate conclusions. The survival benefit of ADT plus Enzalutamide versus ADT alone is probably clinically relevant.

5. ADT plus radiotherapy to the prostate versus ADT alone

In two large trials (N=2,126) the effect of ADT plus radiotherapy versus ADT alone was investigated in newly diagnosed patients: the STAMPEDE H-arm and the HORRAD trial. Patients in the intervention group of the STAMPEDE H-arm trial received 36 Gy, 6 fractions for 6 weeks or 55 Gy, 20 fractions for 4 weeks. In the HORRAD trial, patients in the intervention group received 70 Gy, 35 fractions for 7 weeks or 57.76 Gy, 19 fractions for 6 weeks. Both trials were assessed as methodologically of good quality with a low risk of bias due to study design and conduct.

The data in Table 6 is from Burdett 2019 unless stated otherwise.

Table 6. Results of ADT plus radiotherapy to the prostate versus ADT alone, two trials (HORRAD; Boevé 2019 and STAMPEDE H-arm, Parker 2018).

NA = not available

¹ Data from Wang 2020

² The certainty of the evidence has been lowered by one level due to imprecision (sample size < 2000).

³ The certainty of the evidence has been lowered by one level as the confidence interval encompasses the boundary for clinical decision-making.

⁴ The certainty of the evidence has been lowered by one level due to study limitations (risk of detection bias).

⁵ The certainty of the evidence has been lowered by two levels due to study limitations (risk of detection bias) and imprecision (confidence interval encloses the boundary for clinical decision making).

⁶ Concerns data from the STAMPEDE H-arm. Data from the HORRAD trial on toxicity not yet available.

⁷ Data from the HORRAD trial (Boevé 2021).

⁸The certainty of the evidence has been lowered by two levels due to study limitations (risk of performance and detection bias) and imprecision (sample size from 1 trial and < 2000).

The subgroup analysis was considered relatively convincing and seems to show an interaction between the volume of the disease and the magnitude of effect. There was a clinically relevant survival benefit of ADT plus radiotherapy over ADT alone for the subgroup with low volume disease (although the confidence interval encloses the boundary for clinical decision making, which indicated imprecision in the effect estimate). There is no clinically relevant benefit with respect to disease progression. There is no indication (and this does not seem plausible) that there are substantially fewer complications/side effects. There is no clinically relevant difference in overall quality of life.

Ongoing research

ARASENS: ADT plus darolutamide + docetaxel (6 cycles) vs ADT + docetaxel (6 cycles) (Di

Lorenzo, 2022)

(ARCHES: ADT plus Enzalutamide vs. ADT only)

PEACE-1A1 (NCT01957436): Radiotherapie + ADT/abi vs. ADT/abi only

To answer the clinical question, a systematic literature analysis was carried out to answer the following research question:

What is the effect of ADT combined with an ARSI or chemotherapy or radiation compared to ADT alone in patients with newly diagnosed hormone-sensitive metastatic prostate cancer on survival, disease progression, complications/side effects and quality of life?

P patients: Adult patients (≥18 years) with newly diagnosed metastatic hormone-sensitive prostate cancer; metastatic untreated disease as initial presentation.

I intervention: ARSI, chemotherapy, radiation or other new treatment + ADT.

C control: ADT only.

O outcome measure: Overall survival, progression-free survival, death due to prostate cancer, complications/adverse events, quality of life, radiological progression, clinical progression, PSA progression, time to next treatment, costs.

Relevant subgroups: High volume and low volume hormone sensitive metastatic prostate cancer.

Relevant outcome measures

The working group considered overall survival, progression-free survival (radiological progression, clinical progression, PSA progression) and death from prostate cancer to be crucial outcome measures for decision-making and complications/adverse events and quality of life, as important outcome measures for decision-making. Time to next treatment and costs were considered by the working group as other outcome measures. For the subgroups ‘high volume’ and ‘low volume’ disease overall survival was considered the crucial outcome measure.

The working group defined the crucial and important outcome measures as follows (in analogy with Sathianathen 2020):

Overall survival:                              

Time from randomisation to death from any cause, measured after a minimum follow-up of 3 years (time-to-event outcome, objective outcome).

Progression-free survival:

Time from randomization until clinical, biochemical, or radiographic progression after a minimum follow-up of 3 years (time-to-event outcome, subjective outcome). Biochemical and radiographic progression were defined using the criteria specified by the Prostate CancerWorking Group 2. Clinical progression was defined as clinical deterioration due to cancer.

Death from prostate cancer:

Time from randomization until death from prostate cancer (time-to-event outcome, subjective).

Complications/adverse events:

Lethal/acute/severe, chronic side effects, grade III-V toxicity (dichotomous outcome measure, subjective).

Quality of life:

Overall quality of life at 12 months, or at the time reported in the study; measured with validated instruments, such as the 12-item Short Form (SF-12), 36-item Short Form (SF-36), European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Core Module (QLQ-C30 ), the EORTC Quality of Life Questionnaire Prostate Module [QLQ-PR25]) or the Functional Assessment of Cancer Therapy - Prostate Scales (FACT-P); higher values indicate a better quality of life (continuous outcome measure, subjective).

The working group did not define the outcome measures ‘time to next treatment’ and ‘costs’ a priori, but used the definitions used in the studies. When information on time-to-event outcomes was not available, we attempted to assess the number of events per group (dichotomous outcome, measured at the longest follow-up, at least three years after treatment initiation).

The working group did not define “high” and “low” volume disease, but reported the definitions used in the studies.

The working group defined the following clinically (patient) relevant differences in analogy with the BOM committee (PASKWIL criteria 2016 Palliative treatment):

• Overall survival benefit: >12 weeks or HR <0.7
• Progression-free survival benefit: >12 weeks or HR<0.7

And:

Complications/Adverse Reactions: Lethal: <5% difference; acute/severe: <25% difference

And, in the absence of a clinically relevant difference in overall survival or progression-free survival:

• Improvement in quality of life (10 points or more on the QLQ-C30 QLQ-C30 or a difference of comparable magnitude on other validated quality of life instruments)
• Statistically significant fewer grade 3-4 toxicities affecting daily well-being.

GRADE

GRADE was applied to assess the certainty of the evidence for the main comparisons, subgroups and crucial outcome measures. The credibility of subgroup effects were assessed using the following criteria:

1. Is the subgroup variable a characteristic specified at baseline or after randomization? (subgroup hypotheses should be developed a priori)
2. Is the subgroup difference suggested by comparisons within rather than between studies?
3. Does statistical analysis suggest that chance is an unlikely explanation for the subgroup difference?
4. Did the hypothesis precede rather than follow the analysis and include a hypothesized direction that was subsequently confirmed?
5. Was the subgroup hypothesis one of a smaller number tested?
6. Is the subgroup difference consistent across studies and across important outcomes?
7. Does external evidence (biological or sociological rationale) support the hypothesized subgroup difference?

When subgroup analyses were considered relatively convincing and showed an interaction between the volume of the disease and the magnitude of effect, we only GRADEd the evidence for the subgroups and only presented conclusions for the subgroups.

Search and select (Methods)

On 16 April 2021, the Medline (via OVID) and Embase (via Embase.com) databases were searched with relevant search terms from 2014 onwards for systematic reviews (SRs) and randomized controlled trials (RCTs) about ADT combined with an ARSI or chemotherapy or radiation in patients with hormone-sensitive metastatic prostate cancer. The literature search yielded 490 unique hits. The search justification is displayed under the tab “Verantwoording”. When several publications described the same study, the most recent publication was selected for inclusion. Studies were further selected on the basis of the following selection criteria: patients are adults with hormone-sensitive prostate cancer, the intervention is treatment with a substance or treatment in addition to ADT, and there is a control group for which the treatment consists of ADT only.

Results

Initially, the SRs found were reviewed (118) and assessed for relevance. 28 SRs were selected based on title and abstract. After consulting the full text, one SR was then selected as the basis for the literature summary of the crucial outcome measure ‘overall survival’ (Wang, 2020). This SR turned out to be the most relevant to answer the PICO, because all relevant equations were included. The other SRs were consulted, if necessary, to gather information on other outcome measures.

It was then checked whether any relevant RCTs had been published after the search date of this Wang 2020 (which was 7 May 2020). Eleven RCTs were selected on the basis of title and abstract. After consulting the full text, nine studies were subsequently excluded (see exclusion table under the Justification tab), and two studies were definitively selected and added to the literature analysis. On April 29 2021, 13 days after the search, a relevant study was published: the final analysis of the TITAN trial (Chi, 2021). Because the TITAN trial is the only known study on the effect of adding Apalutamide to ADT, this study was added to the search yield. We did not find relevant data with regard to triple therapy within the medline search. The subgroup analysis within the CHAARTED, STAMPEDE ARCHES, TITAN and ENZAMET trials portended benefit of ARSI after docetaxel upfront https://doi.org/10.1016/j.clgc.2020.05.003. The PEACE-1 and ARASENS both published recently with promising data, but have not been evaluated by the commissie BOM doi: 10.1016/S0140-6736(22)00367-1, https://doi.org/10.1056/NEJMoa2119115. These are interesting data that probably warrant an update in the near future.

The Wang 2020 SR was of good quality and covered the literature until May 2020 (see quality assessment under tab “Verantwoording”). The SR reported on the outcome measures: overall survival, prostate-specific antigen progression-free survival (PSA-PFS), time to symptomatic skeletal events, time to pain progression, and time to chemotherapy. Information on the other crucial and important outcome measures relevant to this guideline module was collected from the following Cochrane reviews:

• Sathianathen 2018 (concerns ADT plus Docetaxel versus ADT alone)
• Sathianathen 2020 (concerning the comparison of ADT plus Abiraterone plus Prednisolone versus ADT alone

and the following SRs:

• Chen 2020 (concerns a network meta-analysis into current systemic combination therapies)
• Burdett 2019 (concerns an SR to radiotherapy for metastatic hormone-sensitive prostate cancer)

And the following original studies, as these were the only studies available for two of the relevant comparisons:

• Chi 2021 (ADT plus Apalutamide versus ADT alone)
• Davis 2019 (ADT plus Enzalutamide versus ADT alone)

We used the information in the SRs to assess the study design (risk of bias) of the individual trials.