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Androgen Receptor Targeted Agents for Castration Resistant Prostate Cancer: A Review of Clinical Effectiveness and Cost-Effectiveness

CADTH Rapid Response Report: Summary with Critical Appraisal

and .

Abbreviations

AA

Abiraterone acetate

ADT

Androgen deprivation therapy

AEs

Adverse events

ALT

Alanine amino transferase

AST

Aspartate amino transferase

ARTA

Androgen receptor targeting agent

BPI-SF

Brief Pain Inventory-Short Form

CI

Confidence interval

CTX

Cabazitaxel

CRPC

Castrate resistant prostate cancer

DTX

Docetaxel

ECG

Electrocardiograms

ECOG

Eastern Cooperative Oncology Group

EOD

Extent of disease

ENZ

Enzalutamide

FACT-P

Functional Assessment of Cancer Therapy-Prostate

GRADE

Grading of Recommendations Assessment, Development, and Evaluation

HR

Hazard ratio

HTA

Health technology assessment

JBI

Joanna Briggs Institute

LDH

Lactate dehydrogenase

MA

Meta-analysis

mCRPC

Metastatic castration-resistant prostate cancer

NA

Not applicable

NR

Not reported

OR

Odds ratio

OS

Overall survival

P

Prednisone

PFS

Progression-free survival

PRISMA

Preferred Reporting Items for Systematic Reviews and MetaAnalyses

PSA

Prostate-specific antigen

QoL

Quality of life

RCT

Randomized controlled trial

SR

Systematic review

Context and Policy Issues

Prostate cancer is the most common cancer in men and is the fourth most common cancer in Canada.1 Approximately 1 in 7 men will be diagnosed with prostate cancer in their lifetime, and 1 in 27 will die from the disease.1,2 However, the age-standardized mortality rate for all stages of prostate cancer have decreased by an average of 2.9% per year, or 41.0% from 1995 to 2012.3,4 The majority (75%) of diagnosed prostate cancer are stage I or stage II (localized), and the age-standardized incidence rate of these cancer stages have decreased by 3.2% per year from 2005 to 2015.4 The age-standardized incidence rate of stage III and IV cancers have remained relatively unchanged.4

Androgen deprivation therapy (ADT) has been the mainstay treatment for metastatic prostate cancer.5 Current ADT approaches include surgical castration or medical castration using a gonadotropin releasing hormone agonist with or without an anti-androgen drug.6 Although over 80% of patients respond to ADT initially, nearly all eventually develop progressive disease following castration, a lethal stage known as metastatic castration-resistant prostate cancer (mCRPC).7 In 2004, docetaxel (DTX) was the first chemotherapy approved by the US Food and Drug Administration for treatment of mCRPC.8,9 Since then, five newly developed agents were approved including a second generation taxane cabazitaxel (CTX),10 cellular immunotherapy sipuleucel-T,11 radiopharmaceutical radium-223,12 and two androgen receptor-targeted agents (ARTA) abiraterone acetate (AA)1315 and enzalutamide (ENZ).16,17

Since ARTA have been demonstrated by recent studies in improving overall survival (OS) in both chemotherapy-pretreated and chemotherapy-naïve patients with mCRPC, both AA and ENZ have been approved as first-line treatment, instead of DTX.1317 However, some patients have rapidly progressed on ARTA treatments despite the initial clinical effectiveness.18 After progression on first-line ARTA, it was unclear which subsequent therapy, such as second-line chemotherapy, an alternative ARTA, or an alternative ARTA with chemotherapy in between, would improve clinical outcomes.

The aim of this report is to review the comparative clinical effectiveness and cost-effectiveness of varying treatment sequences of ARTA in patients with CRPC.

Research Questions

  1. What is the comparative clinical effectiveness of varying treatment sequences of androgen receptor targeted agents in patients with castrate-resistant prostate cancer?
  2. What is the comparative cost-effectiveness of varying treatment sequences of androgen receptor targeted agents in patients with castrate-resistant prostate cancer?

Key Findings

Based on a single well conducted randomized controlled trial, patients who failed on first-line treatment with enzalutamide, subsequent treatment with abiraterone had low response rates, and the combination of enzalutamide and abiraterone was not indicated, owing to observed adverse effects. Likewise, evidence from very low quality non-randomized studies suggests that treatment sequence of enzalutamide-to-abiraterone is less favorable than abiraterone-to-enzalutamide sequence. Also, from very low quality non-randomized studies, subsequent chemotherapy with taxanes appeared to be more effective than alternative second-line androgen receptor targeting agents in treatment of chemotherapy-naïve metastatic castrate-resistant prostate cancer patients who progressed on first-line androgen receptor targeting agents. Due to substantial limitations of the non-randomized studies, these findings should be considered as preliminary and hypothesis generating. No comparative cost-effectiveness studies were identified.

Methods

Literature Search Methods

A limited literature search was conducted by an information specialist on key resources including Ovid Medline, the Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. The search strategy was comprised of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Androgen Receptor Targeted Agents (ARTA) (including berdazimer sodium, ralaniten acetate, enzalutamide, apalutamide, abiraterone, darolutamide, proxalutamide, and seviteronel) and castration resistant prostate cancer (mCRPC). Search filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, or network meta-analyses, randomized controlled trials, controlled clinical trials, or any other type of clinical trial, and economic studies. The search was also limited to English language documents published between January 1, 2014 and May 10, 2019.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1. Selection Criteria.

Table 1

Selection Criteria.

Exclusion Criteria

Studies were excluded if they did not meet the selection criteria in Table 1 and if they were published prior to 2014.

Critical Appraisal of Individual Studies

The critical appraisal checklists of the Joanna Briggs Institute were used to assess the quality of the included RCTs19 and non-randomized studies.20 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 561 citations were identified in the literature search. Following screening of titles and abstracts, 536 citations were excluded and 25 potentially relevant reports from the electronic search were retrieved for full-text review. One potentially relevant publication was retrieved from the grey literature search. Of the 26 potentially relevant articles, 13 publications were excluded for various reasons, while 13 publications including one RCT and 12 non-randomized studies met the inclusion criteria and were included in this report. No economic studies were identified. Appendix 1 presents the PRISMA flowchart21 of the study selection.

Summary of Study Characteristics

The characteristics of the identified RCT22 and non-randomized studies2334 are presented in Appendix 2.

Study Design, Country of Origin, and Year of Publication

The RCT (PLATO study)22 was conducted by authors from North America, Europe and Australia, and was published in 2018. The 12 non-randomized studies2334 were all retrospective chart reviews, which were conducted by authors from Japan23,24,26,2830 and USA,25,27,3134 and were published in 2018,2325 2017,2632 201533 and 2014.34

Population

Ten studies2226,28,29,31,32,34 included patients with chemotherapy-naïve mCRPC and three studies27,30,33 included mCRPC patients previously treated with or without chemotherapy. All patients progressed after first line ARTA and received subsequent treatments (e.g., alternative ARTA, taxane, or taxane followed by alternative ARTA). In all studies, patients had median age of approximately 70 years. Except the RCT, not all patient characteristics in the non-randomized studies were balanced between groups.

Interventions and Comparators

The sequences of treatment in the intervention groups were ENZ-to-ENZ + AA, AA-to-ENZ, and ARTA-to-ARTA. On the Sequence ARTA-to-ARTA, patients who progressed on first-line (i.e., AA or ENZ) received alternative ARTA (i.e., ENZ or AA).

The sequences of treatment in the comparator groups were ENZ-to-AA, ARTA-to-taxane (CTX or DTX), or ARTA-to-taxane-to-ARTA.

Outcomes

The main outcomes evaluated in the included studies were combined progression-free survival (PFS), prostate-specific antigen (PSA) response, time to PSA progression or PSA-PFS, and overall survival (OS).

Combined PFS was defined as the time from the start date of first-line treatment to the date on which disease progression (clinical or radiographic) after treatment with a second-line therapy was observed.

PSA response was defined as the proportion of patients achieved a decline of PSA by ≥ 30% or ≥ 50% from baseline from each line therapy.

Time to PSA progression (also referred as total PSA-PFS) was the sum of time from initiation of each line therapy to PSA progression (defined as a 25% increase in PSA from baseline or nadir PSA).

OS was defined as the time from initiation of the first-line therapy to all-caused death.

Data Analysis and Synthesis

The RCT22 applied sample size calculation and analyzed data using the intention-to-treat approach. All non-randomized studies2334 performed appropriate statistical analyses for comparisons among treatment groups.

Funding

Two studies22,31 were financially supported by pharmaceutical companies, two studies27,33 received support from public funding, and nine studies.2326,2830,32,34 did not report the source of funding.

Summary of Critical Appraisal

Quality assessments of the RCT22 (Table 3) and of the non-randomized studies2334 (Table 4 and Table 5) are presented in Appendix 3.

In the RCT,22 participants were truly randomized to treatment groups, treatment groups were similar at baseline, participants and treatment providers were blinded to treatment assignment, study groups were treated identically other than the intervention of interest, intention-to-treat analysis was applied, outcomes were measured in the same way for both groups using reliable methods, and appropriate statistical analyses were used. It was unclear if allocation to treatment was properly concealed, and whether or not outcomes assessors were blinded to treatment assignment. The quality of this RCT was considered as high.

All non-randomized studies2334 provided appropriate research questions and objectives, had at least one control group, measured the outcomes of participants in the same and reliable way, and used appropriate statistical analysis. In all studies,2334 there were some differences in certain patient characteristics among treatment groups, and it was unclear if participants received similar treatment and care other than the exposure or intervention of interest. Hence, it is possible, that the effect may be explained by the differences between participants or by other exposures or treatments, rather than the intervention of interest. The quality of all included non-randomized studies was considered as very low.

Summary of Findings

Clinical Effectiveness and Safety

The main findings and conclusions of the included studies2234 (Table 6) are presented in Appendix 4.

Comparison 1: ENZ-to-ENZ + AA versus ENZ-to-AA

In the RCT,22 patients with chemotherapy-naïve mCRPC who progressed on first-line ENZ were randomly assigned to receive a combination of ENZ and AA or AA alone as second-line therapy.

Combined PFS

The median of combined PFS was 5.7 months in the ENZ-to-ENZ + AA and 5.6 months in the ENZ-to-AA sequence of treatment groups. No statistically significant difference between groups was observed.

Time to PSA progression

Both groups had similar median time to PSA progression (P = 0.45).

PSA response

During the second-line therapy, 1% of the ENZ-to-ENZ + AA group and 2% of the ENZ-to-AA group had a confirmed decline of ≥ 50% in baseline PSA.

Other outcomes

There were no significant differences between groups for other outcomes such as rate of pain progression, objective response rate, time to first use of subsequent antineoplastic therapy, and time to degradation of FACT-P score.

Safety

Patients in the ENZ-to-ENZ + AA group had higher incidence of grade 3 hypertension and elevated liver enzymes (alanine amino transferase, aspartate amino transferase) than those in the ENZ-to-AA group.

Comparison 2: AA-to-ENZ versus ENZ-to-AA

Six retrospective chart review studies23,27,29,30,32,34 compared the clinical outcomes between AA-to-ENZ and ENZ-to-AA sequential treatment in mCRPC patients. In these studies, patients who failed on first-line ARTA (AA or ENZ) received alternative second-line ARTA (ENZ or AA).

Combined PFS

The median combined PFS was significantly longer in the AA-to-ENZ compared to ENZ-to-AA sequence of treatment as shown in three studies.27,29,30 Two studies23,34 found no significant difference in median combined PFS between groups.

Time to PSA progression

In three studies,27,30,32 the sum of time from initiation of each ARAT agent to PSA progression was significantly longer in the in the AA-to-ENZ compared to ENZ-to-AA sequence of treatment. One study34 found no significant difference in time to PSA progression between groups.

PSA response

Four studies23,27,29,32 found that PSA response rate was not significantly different between AA and ENZ in the first-line therapy, but significant differences were observed to second-line treatment (i.e., higher for ENZ compared to AA). Total PSA response rate was significantly higher in the in the AA-to-ENZ compared to ENZ-to-AA sequence of treatment. One study34 found no significant difference in PSA response between groups.

Overall Survival

Five studies23,27,29,30,32 found no significant difference in OS between AA-to-ENZ and ENZ-to-AA sequence groups.

Safety

One study30 reported adverse events and found no differences in safety profiles between treatment sequences.

Comparison 3: ARTA-to-ARTA versus ARTA-to-Taxane (DTX or CTX)

Four retrospective chart review studies2426,31 compared the clinical outcomes between ARTA-to-ARTA and ARTA-to-Taxane sequential treatment in patients with chemotherapy-naïve mCRPC. In the ARTA-to-ARTA sequence of treatment, patients who progressed on first-line ARTA (AA or ENZ) were treated with alternative second-line ARTA (ENZ or AA). In the ARTA-to-Taxane sequence, patients who progressed on first-line ARTA (AA or ENZ) were put on second-line chemotherapy with DTX or CTX. One study33 with small sample size (n = 9 in AA-to-ENZ; n = 13 in AA-to-DTX) compared the clinical outcomes between AA-to ENZ and AA-to-DTX without using statistical analysis for comparisons.

Combined PFS

One study26 reported combined PFS as an outcome, and found that ARTA-to-DTX had significantly longer combined PSF compared to the ARTA-to-ARTA sequence of treatment. One study,33 without statistical comparison, also reported a longer combined PFS in the AA-to-DTX group compared to AA-to-ENZ group.

Time to PSA progression

The time to PSA progression was reported in two studies24,25 and was significantly longer in the ARTA-to-Taxane (DTX or CTX) compared to ARTA-to-ARTA sequence of treatment. One study,33 without statistical comparison, also reported a longer time to PSA progression in the AA-to-DTX group compared to AA-to-ENZ group.

PSA response

Three studies24,25,31 found that PSA response rate to the second-line therapy was significantly higher with DTX or CTX compared to ARTA, after failure of initial ARTA. One study26 showed that the combined PSA response rate to both lines of treatment was significantly higher in the ARTA-to-DTX compared to ARTA-to-ARTA sequence of treatment. One study,33 without statistical comparison, also reported a higher PSA response rate in the AA-to-DTX group compared to AA-to-ENZ group.

Overall Survival

The median OS duration was shown to be significantly higher in the ARTA-to-DTX group than the ARTA-to-ARTA group in one study,24 but not significantly different between groups in three studies.25,26,31 One study,33 without statistical comparison, reported a longer OS duration in the AA-to-DTX group compared to AA-to-ENZ group. Two studies25,31 performed subgroup analyses and found that patients with poor prognosis (e.g., low hemoglobin, high lactate dehydrogenase, and intermediate-to-high Halabi risk scores) receiving second-line chemotherapy had significantly longer OS compared to those receiving second-line ARTA.

Comparison 4: ARTA-to-ARTA versus ARTA-to-Taxane-to-ARTA

One retrospective chart review study28, with an imbalanced number of patients in each group (n = 173 in ARTA; n = 102 in ARTA-to-ARTA; n = 27 in ARTA-to-Taxane-to-ARTA), investigated whether the use first-line ARTA with or without subsequent chemotherapy could affect the efficacy of the second-line ARTA. Between ARTA-to-ARTA and ARTA-to-Taxane-to-ARTA, there were no significant differences between groups with respect to PSA response rate and time to PSA progression. However, patients receiving subsequent ARTA with or without taxane therapy in between had significantly less clinical benefit than those in the ARTA only group, suggesting cross-resistance between ARTA.

Cost-Effectiveness

No comparative cost-effectiveness studies of different treatment sequences of ARTA in patients with mCRPC were identified; therefore, no summary can be provided.

Limitations

Except the well-conducted RCT, the quality of clinical evidence derived from non-randomized studies, which are of retrospective design, was considered as very low as the studies may have been subjected to multiple biases, including selection bias and information bias. Some patient characteristics (e.g., age, baseline PSA, blood test parameters, time from CRPC to first-line treatment with ARTA, baseline EOD score, time to second line therapy) were significantly different between groups in most studies, together with significant imbalance with respect to sample size in each group in four studies,2628,31 which might result in heterogeneous baseline measurements. The cohorts were relatively small, with no sample size calculation; therefore, the analyses might be underpowered to detect true differences, if any difference existed. The observation period might be too short to detect if there was any difference in terms of OS. It was unclear how first-line therapy was chosen that would impact subsequent therapy. Some factors, including disease severity and rate of disease progression, might have biased the physician in choosing sequential treatment regimens. As therapy information was not reported, administration doses of ARTA and taxanes might vary between groups and among studies, which could have affected the clinical outcomes. Due to limited data availability in retrospective design, not all potential confounding variables could be properly controlled in data analysis. Treatment-related adverse events were not reported in most studies, therefore the comparative safety among treatment sequences was unclear. The findings might not be generalizable to the Canadian context as no identified studies were conducted in Canada.

Conclusions and Implications for Decision or Policy Making

For comparative clinical effectiveness, one RCT22 and 12 non-randomized studies2334 (all of retrospective design) were identified. No comparative cost-effectiveness studies were identified.

Four sets of comparative sequences of ARTA in the treatment of patients with mCRPC were identified and comprised: 1) ENZ-to-ENZ + AA versus ENZ-to-AA; 2) AA-to-ENZ versus ENZ-to-AA; 3) ARTA-to-ARTA versus ARTA-to-Taxane (DTX or CTX); 4) ARTA-to-ARTA versus ARTA-to-Taxane-to-ARTA.

Results from an RCT suggest that AA and prednisone had low response rates in mCRPC patients who progressed after treatment with ENZ, and the combination of ENZ and AA given as second-line therapy resulted in a greater amount of patients experiencing hypertension and elevated liver enzymes. Retrospective studies provided very low quality evidence for the remaining comparative sequences. Between AA-to-ENZ and ENZ-to-AA sequence of treatment, AA-to-ENZ sequence appeared to be more favorable than ENZ-to-AA sequence in patients with mCRPC regarding the improved clinical outcomes such as combined PFS, time to PSA progression and PSA response rate, but not OS. Between ARTA-to-ARTA and ARTA-to-Taxane (DTX or CTX), ARTA-to-Taxane appeared to be more effective than ARTA-to-ARTA treatment sequence in patients with chemotherapy-naïve mCRPC regarding the improved clinical outcomes such as combined PFS, time to PSA progression and PSA response rate. Patients with poor prognosis receiving second-line chemotherapy might have improved OS compared to those receiving ARTA. One retrospective chart review did not find any differences between ARTA-to-ARTA and ARTA-to-Taxane-to-ARTA respect to PSA response rate and time to PSA progression. Given the aforementioned limitations of the retrospective studies, their findings should be considered as preliminary and hypothesis generating. Prospective controlled trials with high degree of internal validity and adequate power are required to draw definitive conclusions.

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Appendix 1. Selection of Included Studies

Image app1f1

Appendix 2. Characteristics of Included Studies

Table 2Characteristics of Included Primary Studies

First Author, Publication Year, Country, FundingStudy Design and AnalysisPatient CharacteristicsInterventionsComparatorsClinical Outcomes

Attard et al., 201822

PLATO

North America, Europe and Australia

Funding: Pharmaceutical companies

Multisite, double-blinded, parallel, 1:1, RCT

Intention-to-treat analysis: Yes

Sample size calculation: Yes

Men with chemotherapy-naïve mCRPC who progressed on ENZ

Median age (years):

ENZ→ENZ + AA/P: 72

ENZ→Placebo + AA/P: 71

Median PSA (µg/L):

ENZ→ENZ + AA/P: 14.4

ENZ→Placebo + AA/P: 11.0

Median testosterone (nmol/L):

ENZ→ENZ + AA/P: 1.2

ENZ→Placebo + AA/P: 1.2

Median LDH (U/L):

ENZ→ENZ + AA/P: 180.5

ENZ→Placebo + AA/P: 176.0

No significant difference between groups in metastatic site, ECOF performance status, and BPI-SF

ENZ→ENZ + AA/P (n = 126)

After developing PSA progression on ENZ (160 mg orally once daily), patients were assigned to ENZ (160 mg daily) + AA (1,000 mg orally once daily) and P (5 mg orally twice daily)

ENZ→Placebo + AA/P (n = 125)

After developing PSA progression on ENZ (160 mg orally once daily), patients were assigned to placebo + AA (1,000 mg orally once daily) and P (5 mg orally twice daily)

Primary:

PFSa (combined PFS [clinical or radiographic])

Secondary:

Time to PSA progression (a 25% increase in PSA from baseline or nadir, also called PSA-PFS)

PSA response of ≥ 50%

PSA response of ≥ 30%

Rate of pain progression

Objective response rate

Time to first use of subsequent antineoplastic therapy

Time to degradation of FACT-P score

Safety (AEs, clinical laboratory tests, physical examinations, vital signs, 12 lead ECGs)

Matsubara et al., 201823

Japan

Funding: NR

Retrospective cohort

Appropriate statistical methods used: Yes

Sample size calculation: No

Men with chemotherapy-naïve mCRPC who progressed on AA or ENZ, then were treated with alternative ARTA (AA or ENZ)

Median age (years):

AA→ENZ: 73.5

ENZ→AA: 76.0

Median time to CRPC (month)

AA→ENZ: 13.2

ENZ→AA: 8.9

Median time from CRPC to AA or ENZ (months)

AA→ENZ: 8.9

ENZ→AA: 12.5

No significant difference between groups in median age, prior radical local treatment, Gleason score, median time from CRPC to AA or ENZ, median number of previous treatment lines with vintage hormonal agents, ECOG performance status, metastatic site, and clinical laboratory tests, excluding PSA.

Significant difference between groups in median time to CRPC, and median PSA.

AA→ENZ (n = 50)

Dosage: NR

ENZ→AA (n = 47)

Dosage: NR

Combined PFSc (clinical or radiographic)

PSA response (a decline of ≥ 50% from baseline)

OSe

Miyake et al., 201824

Japan

Funding: NR

Retrospective cohort

Appropriate statistical methods used: Yes

Sample size calculation: No

Men with chemotherapy-naïve mCRPC who progressed after first-line ARTA (AA or ENZ) received second-line chemotherapy (DTX or alternative ARTA

Mean age (years):

ARTA→ARTA: 75.6

ARTA→DTX: 74.4

Mean ADT duration (months):

ARTA→ARTA: 18.2

ARTA→DTX: 18.6

Mean baseline PSA (mg/mL):

ARTA→ARTA: 23.36

ARTA→DTX: 28.9

Significant difference between groups in mean baseline PSA

No significant difference between groups in age, mean ADT duration, ECOG performance status, and metastatic site

ARTA→ARTA (n = 108)

Dosage: NR

ARTA→DTX (n = 114)

Dosage: NR

PSA response (a decline of >0, ≥ 30%, ≥ 50% from baseline)

Time to PSA progression (PSA-PFS)

OS

Oh et al., 201825

USA

Funding: Pharmaceutical companies

Retrospective cohort

Appropriate statistical methods used: Yes

Sample size calculation: No

Men with chemotherapy-naïve mCRPC who progressed after first-line ARTA (AA or ENZ) received second-line chemotherapy (DTX or CTX) or alternative ARTA

Mean age (years):

ARTA→ARTA: 77.7

ARTA→DTX or CTX: 72.7

Significant difference between groups in most patient characteristics

ARTA→ARTA (n = 198)

Dosage: NR

ARTA→DTX or CTX (n = 147)

Dosage: NR

PSA response (a decline of ≥ 50% from baseline)

Time to PSA progression (a 25% increase in PSA from baseline or nadir, also called PSA-PFS)

OS

Clinical responsef

Time to next therapyg

Pain

Symptomatic skeletal events

Matsubara et al., 201726

Japan

Funding: NR

Retrospective cohort

Appropriate statistical methods used: Yes

Sample size calculation: No

Men with chemotherapy-naïve mCRPC who progressed on first-line ARTA (AA or ENZ) received second-line ARTA or DTX

Median age (years):

ARTA→ARTA: 75

ARTA→DTX: 68

Median time to CRPC (month)

ARTA→ARTA: 12.4

ARTA→DTX: 11.3

Median time from CRPC to AA or ENZ (months)

ARTA→ARTA: 3.0

ARTA→DTX: 2.0

Significant difference between groups in terms of age, median time from CRPC to AA or ENZ, median number of previous treatment lines with vintage hormonal agents, EOD score, lymph node metastasis, and median albumin concentration.

ARTA (AA or ENZ)→ARTA (AA or ENZ) (n = 97)

Dosage: NR

ARTA (AA or ENZ)→DTX (n = 42)

Dosage: NR

Primary:

Combined PFSc (clinical or radiographic)

Secondary:

PSA response (a decline of ≥ 50% from baseline)

OSe

Maughan et al., 201727

USA

Funding: National Institute of Health

Retrospective cohort

Appropriate statistical methods used: Yes

Sample size calculation: No

Men with mCRPC with or without chemotherapy received sequential treatment with AA followed by ENZ or vice versa

Median age (years):

AA→ENZ: 63

ENZ→AA: 62

Median PSA at diagnosis (mg/mL):

AA→ENZ: 18.9

ENZ→AA: 11.3

Median PSA prior to first agent in sequence (ng/mL):

AA→ENZ: 33.0

ENZ→AA: 29.8

No significant difference between groups in reported patient characteristics including ECOG performance status, symptom, Gleason score, and metastatic site.

AA→ENZ (n = 65)

Dosage: NR

ENZ→AA (n = 16)

Dosage: NR

Combined PFS (clinical or radiographic)

OS

Time to PSA progression (a 25% increase in PSA from baseline or nadir, also called PSA-PFS)

PSA response (a decline of ≥ 50% from baseline)

Miyake et al., 201728

Japan

Funding: NR

Retrospective cohort

Appropriate statistical methods used: Yes

Sample size calculation: No

Men with chemotherapy-naïve mCRPC who were treated with a single ARTA (AA or ENZ), or were sequentially treated with ARATs with or without taxane (chemo) therapy in between.

Mean age (years): 77.1

Mean duration of primary ADT (days): 558

Mean PSA (ng/mL): 22.4

Not reported on characteristics among groups

ARTA (AA or ENZ)→ARTA (AA or ENZ) (n = 102)

Dosage: NR

ARTA (AA or ENZ)→Taxane→ARTA (AA or ENZ) (n = 27)

ARAT as first-line (n = 173)

Dosage: NR

PSA response (a decline of ≥ 50% from baseline)

Time to PSA progression (a 25% increase in PSA from baseline or nadir, also called PSA-PFS)

Miyake et al., 201729

Japan

Funding: NR

Retrospective cohort

Appropriate statistical methods used: Yes

Sample size calculation: No

Men with chemotherapy-naïve mCRPC who progressed on first-line ARTA (AA or ENZ) received second-line alternative ARTA

Mean age (years)

AA→ENZ: 75.2

ENZ→AA: 76.0

Mean duration of ADT (months)

AA→ENZ: 18.0

ENZ→AA: 18.3

Mean baseline PSA (ng/mL)

AA→ENZ: 23.2

ENZ→AA: 23.4

No significant difference between groups in reported patient characteristics including ECOG performance status, symptom, Gleason score, and metastatic site.

AA→ENZ (n = 49)

Dosage: NR

ENZ→AA (n = 59)

Dosage: NR

PSA response (a decline of ≥ 50% from baseline)

Combined PFS (clinical or radiographic)

OS

Mori et al., 201730

Japan

Funding: NR

Retrospective cohort

Appropriate statistical methods used: Yes

Sample size calculation: No

Men with mCRPC with or without chemothrapy received sequential treatment with AA followed by ENZ or vice versa

Median age (years):

AA→ENZ: 75

ENZ→AA: 75

Median observation period (months):

AA→ENZ: 13.5

ENZ→AA: 14

Baseline PSA (ng/mL):

AA→ENZ: 51.1

ENZ→AA: 114.9

Median duration of primary ADT (months):

AA→ENZ: 21

ENZ→AA: 15.5

No significant difference between groups in most patient characteristics, except hemoglobin level

AA→ENZ (n = 46)

AA:1,000 mg/day + P (10 mg/day)

ENZ: 160 mg/day

ENZ→AA (n = 23)

Primary:

Combined PFS (clinical or radiographic)

Secondary:

PSA response (a decline of ≥ 50% from baseline)

Time to PSA progression (a 25% increase in PSA from baseline or nadir, also called PSA-PFS)

OS

AE

Oh et al., 201731

USA

Funding: Pharmaceutical companies

Retrospective cohort

Appropriate statistical methods used: Yes Sample size calculation: No

Men with chemotherapy-naïve mCRPC who progressed after first-line ARTA (AA or ENZ) received second-line chemotherapy (DTX or CTX) or alternative ARTA

Mean age (years):

ARTA→ARTA: 73.3

ARTA→DTX or CTX: 77.7

Significant difference between groups in most patient characteristics

ARTA→ARTA (n = 340)

Dosage: NR

ARTA→DTX or CTX (n = 206)

Dosage: NR

OS

Clinical responsef

PSA response (a decline of ≥ 50% from baseline)

Terada et al., 201732

USA

Funding: NR

Retrospective cohort

Appropriate statistical methods used: Yes

Sample size calculation: No

Men with chemotherapy-naïve mCRPC who progressed on first-line ARTA (AA or ENZ), then were treated with second-line ARTA

Age (years): NR

Median PSA at start of first agent (ng/mL)

AA→ENZ: 24.1

ENZ→AA: 17.0

No significant difference between groups in metastasis, ECOF performance status, Gleason score, median PSA at start of first agent, metastatic site

Significant difference between groups in number of patients chosen from different institutions, and number of prior anti-androgen treatment

AA→ENZ (n = 113)

Dosage: NR

ENZ→AA (n = 85)

Dosage: NR

Time to PSA progression (> 25% relative to baseline)

PSA response (a decline of ≥ 50% from baseline)

OSe

Zhang et al., 201533

USA

Funding: Prostate Cancer Foundation and Department of Defense

Retrospective cohort

Appropriate statistical methods used: Yes

Sample size calculation: No

Men mCRPC with or without chemotherapy, who progressed on AA, received ENZ, DTX, or DTX then ENZ

Age: NR

Statistics were not provided for comparisons between groups in patient characteristics

AA→ENZ (n = 9)

Dosage: NR

AA→DTX (n = 13)

AA→DTX→ENZ (n = 19)

Dosage: NR

PSA response (a decline of ≥ 50% from baseline)

Time to PSA progression

OS

Combined PFS (clinical or radiographic)

Suzman et al., 201434

USA

Funding: NR

Retrospective cohort

Appropriate statistical methods used: Yes

Sample size calculation: No

Men with chemotherapy-naïve mCRPC who progressed on AA received either ENZ or DTX

Mean age (years):

AA→ENZ: 70.6

AA→DTX: 68.3

No significant difference between groups in age, Gleason score, and ECOG performance status

Significant difference between groups in metastatic site, baseline PSA, and number of PSAs in 6 months after initiation of therapy

AA→ENZ (n = 30)

Dosage: NR

AA→DTX (n = 31)

Dosage: NR

PSA response (a decline of ≥ 30%, ≥ 50% from baseline)

Time to PSA progression (a 25% increase in PSA from baseline or nadir, also called PSA-PFS)

Combined PFS (clinical or radiographic)

AA = abiraterone acetate; ADT = androgen deprivation therapy; AEs = adverse events; ARTA = androgen receptor targeting agent; BPI-SF = Brief Pain Inventory-Short Form; CRPC = castrate resistant prostate cancer; CTX = cabazitaxel; DTX = docetaxel; ECG = electrocardiograms; ECOG = Eastern Cooperative Oncology Group; EOD = extent of disease; ENZ = enzalutamide; FACT-P = Functional Assessment of Cancer Therapy-Prostate; mCRPC = metastatic castration-resistant prostate cancer; NR = not reported; OS = overall survival; P = prednisone; PFS = progression-free survival; PSA = prostate-specific antigen; QoL = quality of life

a

PSF = Time from random assignment to the first of the following events assessed by the investigator: radiographic progression, unequivocal clinical progression,b or death during study (i.e., death from random assignment to within 112 days [i.e., four cycles] of treatment discontinuation without objective evidence of radiographic progression)

b

Unequivocal clinical progression = Any of the following: new onset of prostate cancer pain requiring chronic opiate use as defined previously, deterioration of ECOG performance status to ≥ 3 as a result of prostate cancer, initiation of cytotoxic chemotherapy for prostate cancer, or radiation therapy or surgical intervention because of complications of tumor progression

c

Combined PSF = Time from the start date of the first-line treatment to the date on which disease progressiond after treatment with a second-line therapy was observed

d

Disease progression: increasing PSA and radiographic progression according to the Prostate Cancer Working Group 2 or 3 criteria at that time, and symptom deterioration caused by prostate cancer

e

OS = Time from initiation of AA or ENZ treatment to death from any cause

f

Clinical response = Improvement in clinical parameters reflecting QoL: a ≥ 1 point reduction in the ECOG performance score, a 5% increase in weight, or 2 g/dL increase in hemoglobin, over a course of ≥ 3 months

g

Time to next therapy = Time from second-line therapy initiation to administration of a different therapy of interest

Appendix 3. Quality Assessment of Included Studies

Table 3Quality Assessment of Randomized Controlled Trial

JBI Critical Appraisal Checklist for RCT19Attard et al., 201822
1. Was true randomization used for assignment of participants to treatment groups?Yes
2. Was allocation to treatment groups concealed?Unclear
3. Were treatment groups similar at the baseline?Yes
4. Were participants blind to treatment assignment?Yes
5. Were those delivering treatment blind to treatment assignment?Yes
6. Were outcomes assessors blind to treatment assignment?Unclear
7. Were treatment groups treated identically other than the intervention of interest?Yes
8. Was follow up complete and if not, were differences between groups in terms of their follow up adequately described and analyzed?Yes
9. Were participants analyzed in the groups to which they were randomized?Yes
10. Were outcomes measured in the same way for treatment groups?Yes
11. Were outcomes measured in a reliable way?Yes
12. Was appropriate statistical analysis used?Yes
13. Was the trial design appropriate, and any deviations from the standard RCT design (individual randomization, parallel groups) accounted for in the conduct and analysis of the trial?Yes

JBI = Joanna Briggs Institute; RCT = randomized controlled trial

Table 4Quality Assessment of Non-Randomized Studies

JBI Critical Appraisal Checklist for Non-Randomized Studies20Matsubara et al., 201823Miyake et al., 201824Oh et al., 201825Matsubara et al., 201726Maughan et al., 201727Miyake et al., 201728
1. Is it clear in the study what is the ‘cause’ and what is the ‘effect’ (i.e. there is no confusion about which variable comes first)?YesYesYesYesYesYes
2. Were the participants included in any comparisons similar?NoNoNoNoNoNo
3. Were the participants included in any comparisons receiving similar treatment/care, other than the exposure or intervention of interest?UnclearUnclearUnclearUnclearUnclearUnclear
4. Was there a control group?YesYesYesYesYesYes
5. Were there multiple measurements of the outcome both pre and post the intervention/exposure?NANANANANANA
6. Was follow up complete and if not, were differences between groups in terms of their follow up adequately described and analyzed?NANANANANANA
7. Were the outcomes of participants included in any comparisons measured in the same way?YesYesYesYesYesYes
8. Were outcomes measured in a reliable way?YesYesYesYesYesYes
9. Was appropriate statistical analysis used?YesYesYesYesYesYes

JBI = Joanna Briggs Institute; NA = not applicable

Table 5Quality Assessment of Non-Randomized Studies (continued)

JBI Critical Appraisal Checklist for Non-Randomized Studies20Miyake et al, 201729Mori et al., 201730Oh et al., 201731Teerada et al., 201732Zhang et al., 201533Suzman et al., 201434
1. Is it clear in the study what is the ‘cause’ and what is the ‘effect’ (i.e. there is no confusion about which variable comes first)?YesYesYesYesYesYes
2. Were the participants included in any comparisons similar?UnclearNoNoNoNoNo
3. Were the participants included in any comparisons receiving similar treatment/care, other than the exposure or intervention of interest?UnclearUnclearUnclearUnclearUnclearUnclear
4. Was there a control group?YesYesYesYesYesYes
5. Were there multiple measurements of the outcome both pre and post the intervention/exposure?NANANANANANA
6. Was follow up complete and if not, were differences between groups in terms of their follow up adequately described and analyzed?YesYesYesYesYesYes
7. Were the outcomes of participants included in any comparisons measured in the same way?YesYesYesYesYesYes
8. Were outcomes measured in a reliable way?YesYesYesYesYesYes
9. Was appropriate statistical analysis used?YesYesYesYesYesYes

JBI = Joanna Briggs Institute; NA = not applicable

Appendix 4. Main Study Findings and Author’s Conclusions

Table 6Summary of Findings of Included Primary Studies

Main Study FindingsAuthor’s Conclusions
Attard et al., 201822

ENZ→ENZ + AA/P (n = 126) versus ENZ→Placebo + AA/P (n = 125)

Treatment duration in period two (median, months)

5.6 versus 5.6

Combined PFS (median, months); clinical or radiographic

5.7 versus 5.6

HR (95% CI) = 0.83 (0.61 to 1.12); P = 0.22

PSA response (%) to second line therapy; a decline of ≥ 50% from baseline

1% (1/124) versus 2% (3/122)

Time to PSA progression or PSA-PFS (median, months); a 25% increase in PSA from baseline or nadir

2.8 versus 2.8

HR (95% CI) = 0.87 (0.62 to 1.24); P = 0.45

Other secondary outcomes (i.e., rate of pain progression, objective response rate, time to first use of subsequent antineoplastic therapy, time to degradation of FACT-P score): No significant difference between groups

Safety

Grade 3 hypertension: 10% versus 2%

Increased ALT: 6% versus 2%

Increased AST: 2% versus 0%

“Combining enzatulamide with abiraterone acetate and prednisone is not indicated after PSA progression during treatment with enzatulamide alone; hypertension and elevated liver enzymes are more frequent with combination therapy”22 p.2639
Matsubara et al., 201823

AA→ENZ (n = 50) versus ENZ→AA (n = 47)

Follow-up periods (median, months)

15.5 versus 19.0

PSA response

to first-line treatment: AA (48%) versus ENZ (51%); P = 0.840

to second-line treatment: AA (6.4%) versus ENZ (30%); P = 0.004

to both lines of treatment: 18% versus 2.1%; P = 0.016

Combined PFS (median, months); clinical or radiographic

11.1 versus 9.04

HR (95% CI) = 0.71 (0.46 to 1.08); P = 0.105

OS (median; months)

25.4 versus 24.2

HR (95% CI) = 0.98 (0.64 to 1.528); P = 0.834

“In conclusion, this retrospective multi-center analysis revealed the cross-resistance between AA and ENZ, and no significant differences were observed in terms of the first-line and second line PFS, combined PFS, and OS between AA-AEZ and ENZ-AA sequences.”23 p. 148
Miyake et al., 201824

ARTA (AA or ENZ)→ARTA (n = 108) versus ARTA→DTX (n= 114)

PSA response (%) to second-line therapy

a decline of >0% from baseline: 50 versus 70.2; P = 0.021

a decline of ≥ 30% from baseline: 33.3 versus 52.6; P = 0.0037

a decline of ≥ 50% from baseline: 21.3 versus 42.1; P < 0.001

Time to PSA progression or PSA-PFS (median, months)

4.2 versus 7.2; P < 0.001

OS (median; months)

14.5 versus 17.5; P = 0.023

“Favorable oncologic outcomes can be expected with DTX treatment, rather than with alternative ARTA, for mCRPC patients after failure of an initial ARTA.”24 p.219
Oh et al., 201825

ARTA (AA or ENZ)→ARTA (n = 198) versus ARTA→ DTX or CTX (n = 147)

PSA response (%) to second-line therapy; a decline of ≥ 50% from baseline

24.6 versus 40.9

Adjusted OR = 2.27; P = 0.005

Time to PSA progression or PSA-PFS (median, months)

4.2 versus 6.0

Adjusted HR = 0.66; P = 0.010

OS (median; months)

11.8 versus 13.1

Adjusted HR = 0.81; P = 0.148

OS (median; months) among poor prognosis patients

low hemoglobin (< 11 g/dL): Adjusted HR = 0.41; P = 0.002

high LDH (> upper limit of normal): Adjusted HR = 0.18; P = 0.014

low albumin (< 1 × lower limit of normal): Adjusted HR = 0.42; P = 0.020

intermediate-to-high Halabi risk scores: Adjusted HR = 0.55; P = 0.009

Clinical response (%)

31.8% versus 50.7%

Adjusted OR = 1.78; P = 0.020

Time to next therapy (months)

15.3 versus 9.3

Opioid use for pain

Adjusted OR = 1.35; P = 0.846

Symptomatic skeletal events

Adjusted OR = 0.33; P = 0.066

“Following progression on first-line ARTA, second-line chemotherapy may be more beneficial in mCRPC compared with second-line ARTA in patients with poor prognosis.”25 p.500e.1
Matsubara et al., 201726

ARTA (AA or ENZ)→ARTA (n = 97) versus ARTA→DTX (n = 42)

Combined PFS (median, months); clinical or radiographic

9.68 versus 12.42

HR (95% CI) = 0.51 (0.33 to 0.80); P = 0.004

PSA response (%) to both lines of treatment; a decline of ≥ 50% from baseline

10.3 versus 21.4; P = 0.080

OS (median; months)

24.71 versus 27.93

HR (95% CI) = 0.60 (0.34 to 1.09); P = 0.095

“ARTA-DTX might improve clinical outcomes in terms of second-line PFS and combined PFS, compared with ARTA-ARTA sequence. However, this significance was not observed for OS.”26 p.e1073
Maughan et al., 201727

AA→ENZ (n = 65) versus ENZ→AA (n = 16)

Combined PFS (median, months); clinical or radiographic

19.5 versus 13.0

Univariate analysis: HR (9% CI) = 0.58 (0.36 to 0.94); P = 0.03

Multivariate analysis: HR (95% CI) = 0.37 (0.22 to 0.64); P < 0.001

OS (median; months)

33.3 versus 29.9

Univariate analysis: HR (9% CI) = 0.74 (0.40 to 1.38); P = 0.35

Multivariate analysis: HR (95% CI) = 0.57 (0.29 to 1.11); P =0.98

Time to PSA progression or PSA-PFS (median, months)

17.5 versus 12.3

Univariate analysis: HR (95% CI) = 0.56 (0.35 to 0.90); P = 0.02

Multivariate analysis: HR (95% CI) = 0.44 (0.26 to 0.74); P =0.002

PSA response (%) to both lines of treatment; a decline of ≥ 50% from baseline

33.8 versus 6.3; P = 0.03

“We observed differences suggesting improved outcomes favoring the abiraterone-to-enzalutamide sequence in men with mCRPC, with statistical confirmation in terms of PFS but not OS.”27 p.33
Miyake et al., 201728

ARTA (n = 173) versus ARTA (AA or ENZ)→ARTA (n = 102) versus ARTA→Taxane→ARTA (n = 27)

PSA response (%) to both lines of treatment; a decline of ≥ 50% from baseline

63.6 versus 20.6 versus 29.6

ARTA versus ARTA→ARTA; P < 0.001

ARTA versus ARTA→Taxane→ARTA; P = 0.0018

ARTA→ARTA versus ARTA→Taxane→ARTA; P = 0.46

Time to PSA progression or PSA-PFS (median, months)

10.8 versus 4.7 versus 4.1

ARTA versus ARTA→ARTA; P < 0.001

ARTA versus ARTA→Taxane→ARTA; P < 0.001

ARTA→ARTA versus ARTA→Taxane→ARTA; P = 0.80

“In conclusion, cross-resistance between the ARTA may be commonly observed in patients with mCRPC, irrespective of the use of taxanes between the ARTA therapies; accordingly, following the failure of either ARTA, the sequential administration of another ARTA should be avoided.”28 p.e221
Miyake et al., 201729

AA→ENZ (n = 49) versus ENZ→AA (n = 59)

PSA response (%) to both lines of treatment; a decline of ≥ 50% from baseline

18.4 versus 5.1; P = 0.029

Combined PFS (median, months)

18.4 versus 12.8

HR (95% CI) = 0.44 (0.37 to 0.81); P = 0.0091

OS (median; months)

Not reached versus 22.1

HR (95% CI) = 0.80 (0.27 to 1.31); P = 0.21

“Although cross-resistance between ARTA is a common phenomenon in docetaxel-naïve patients with mCRPC, different efficacies were observed favoring the AA-to-Enz rather than ENZ-to-AA sequence in this series with respect to combined PSA PFS but not OS.”29 p.e591
Mori et al., 201730

AA→ENZ (n = 46) versus ENZ→AA (n = 23)

Combined PFS (median, months)

Not reached versus 11; P = 0.043

Univariate analysis: HR (95% CI) = 0.44 (0.19 to 1.01); P = 0.054

Multivariate analysis: HR (95% CI) = 0.39 (0.15 to 1.03); P = 0.056

Combined PFS was significantly longer (17 months versus 8 months; P = 0.015) among patients with low LDH (< 210 IU/L) compared to those with high LDH (≥210 IU/L)

Time to PSA progression or PSA-PFS (median, months)

Longer in AA→ENZ group; P = 0.049

OS (median; months)

No significant difference between groups; P = 0.62

Univariate analysis: HR (95% CI) = 0.79 (0.31 to 2.02); P = 0.63

Adverse events

No significant difference between groups

“The results of this study suggested the AA-ENZ sequence had longer combined PFS and total PSA-PSF compared to ENZ-AA sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS.”30 p.1144
Oh et al., 201731

ARTA (AA or ENZ)→ARTA (n = 340) versus ARTA→ DTX or CTX (n = 206)

OS (median; months)

12.2 versus 13.3

Adjusted HR (95% CI) = 0.90 (0.65 to 1.24); P = 0.511

OS (median; months) among poor prognosis patients

low hemoglobin (< 11 g/dL): Adjusted HR (95% CI) = 0.52 (0.34 to 0.82); P = 0.004

low albumin (< 1 × lower limit of normal): Adjusted HR (95% CI) = 0.36 (0.19 to 0.70); P = 0.003

intermediate-to-high Halabi risk scores: Adjusted HR (95% CI) = 0.71 (0.48 to 1.06); P = 0.094

Clinical response (%) to second-line therapy

34.0% versus 50.5%

Adjusted OR (95% CI) = 1.54 (0.99 to 2.32); P = 0.054

PSA response (%) to second-line therapy; a decline of ≥ 50% from baseline

29.9 versus 45.3

Adjusted OR (95% CI) = 2.08 (1.20 to 3.62); P = 0.009

“Taken together, these findings suggest that after first-line AR-targeted therapy second-line chemotherapy, versus alternative AR-targeted therapy, may be associated with improved treatment outcomes, particularly among patients with worse disease prognosis.”31 p.56
Terada et al., 201732

AA→ENZ (n = 113) versus ENZ→AA (n = 85)

PSA response (%); a decline of ≥ 50% from baseline

First-line: AA (48%); ENZ (55%); P = 0.353

Second-line: ENZ (29%); AA (13%); P = 0.011

AA→ENZ was more effective than ENZ→AA

Time to PSA progression or PSA-PFS (median, days)

455 versus 296

HR (95% CI) = 0.67 (0.41 to 0.76); P < 0.001

Multivariate analysis: HR (95% CI) = 0.65 (0.42 to 0.99); P = 0.044

OS (median; days)

919 versus 899

HR (95% CI) = 0.88 (0.53 to 1.43); P = 0.599

Multivariate analysis: HR (95% CI) = 0.81 (0.49 to 1.35); P = 0.427

“The abiraterone-to-enzalutamide sequence might have more favorable efficacy in terms of combined prostate-specific antigen progression-free survival than the enzalutamide-to abiraterone sequence, although no differences in overall survival were observed. This could possibly be attributable to longer prostate-specific antigen progression-free survival with second line enzalutamide compared with abiraterone.”32 p.441
Zhang et al., 201533

AA→ENZ (n = 9) versus AA→DTX (n = 13) versus AA→DTX→ENZ (n = 19)

PSA response (%) to second-line therapy; a decline of ≥ 50% from baseline

11% versus 55% versus 5%

Time to PSA progression or PSA-PFS (median, months)

4.0 versus 5.6 versus 3.0

Combined PFS (median, months)

3.7 versus 5.1 versus 2.8

OS (median; months)

8.5 versus “not estimable” versus 9.6

“In this chart review of consecutive men with progressive mCRPC after AA, we found modest activity for enzalutamide and docetaxel, with clear cross-resistance for AA and enzalutamide.”33 p.392
Suzman et al., 201434

AA→ENZ (n = 30) versus AA→DTX (n = 31)

PSA response to second-line therapy; a decline of ≥ 50% from baseline

OR (95% CI) = 1.68 (0.51 to 5.66); P = 0.40

Time to PSA progression or PSA-PFS (median, months)

4.1 versus 4.1; P = 0.327

HR (95% CI) = 1.35 (0.53 to 3.66); P =0.502

Combined PFS (median, months)

4.7 versus 4.4

HR (95% CI) = 1.44 (0.77 to 2.71); P = 0.257

“Treatment with either enzalutamide or docetaxel produces modest PSA responses and PFS intervals in this abiraterone-pretreated mCRPC population. In this retrospective study with small sample size, no significant differences in outcomes were observed between groups. Therefore, either enzalutamide or docetaxel may be a reasonable option in men who have progressed on abiraterone.”34 p.1278

AA = abiraterone acetate; ALT = alanine amino transferase; ARTA = androgen receptor-targeted agent; AST = Aspartate amino transferase; CTX = cabazitaxel; DTX = docetaxel; ENZ = enzalutamide; FACT-P: Functional Assessment of Cancer Therapy-Prostate; HR = hazard ratio; LDH = lactate dehydrogenase; OR = odds ratio; OS = overall survival; P = prednisone; PFS = progression free survival

About the Series

CADTH Rapid Response Report: Summary with Critical Appraisal
ISSN: 1922-8147

Version: 1.0

Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.

Suggested citation:

Androgen Receptor Targeted Agents for Castration Resistant Prostate Cancer: A Review of Clinical Effectiveness and Cost-Effectiveness. Ottawa: CADTH; 2019 Jun. (CADTH rapid response report: summary with critical appraisal).

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Bookshelf ID: NBK545596PMID: 31449370

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