Survival Trend in Individuals With De Novo Metastatic Prostate Cancer After the Introduction of Doublet Therapy

This cohort study investigates if the introduction of doublet therapy is associated with changes in survival in individuals with de novo metastatic castration-sensitive prostate cancer.


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Author affiliations and article information are listed at the end of this article.in the LATITUDE trial, median overall survival was 53.3 months in men with de novo metastatic highrisk cancer treated with doublet therapy with abiraterone acetate, compared with 36.5 months in the placebo group. 7Novel ARPis such as enzalutamide and apalutamide, when combined with ADT, have also been demonstrated to significantly increase progression-free survival 11 and overall survival. 8,9nsequently, guidelines from the European Association of Urology and the National Swedish Guidelines now recommend doublet therapy for men with mCSPC. 12,13As a result, use of doublet therapy has increased substantially in Sweden, and in 2021 approximately half of all individuals with de novo mCSPC received doublet therapy.At the same time, earlier detection of metastatic disease has led to lower tumor burden in patients with de novo mCSPC, as mirrored by lower prostatespecific antigen (PSA) levels at diagnosis. 14The aim of this study was to investigate if the increased use of doublet therapy in men with de novo mCSPC in Sweden has been accompanied by improvements in survival, taking other temporal changes into consideration.

Methods
The National Prostate Cancer Register (NPCR) of Sweden captures 98% of all incident prostate cancer cases compared with the Swedish Cancer Registry to which reporting is mandated by law. 15In

Study Population
The study population consisted of men registered from 2008 to 2020 in NPCR with de novo mCSPC defined by the presence of skeletal or visceral metastases on radionuclide bone scan, computed tomography, positron emission tomography (PET)/computed tomography, magnetic resonance imaging, or radiograph imaging.

Exposure
Data on use of the ARPi drugs abiraterone (Anatomical Therapeutic Chemical code L02BX03), enzalutamide (L02BB04), and apalutamide (L02BB05) were based on filled prescriptions for these

Statistical Analysis
Survival was estimated annually and in 3 calendar periods corresponding to the gradual uptake of doublet therapy, ie, 2008 to 2012, 2013 to 2016, and 2017 to 2020.All analyses were stratified according to age at diagnosis (<60, 60-69, 70-79, and Ն80 years).Crude survival was described with Kaplan-Meier curves.Differences in survival due to heterogeneous treatment intensity over calendar periods were expected to become evident after 6 months from start of treatment so hazards were not expected to be proportional. 19We estimated standardized survival curves using a parametric gamma survival model allowing for nonproportional hazards, comparing the 3 study periods. 20We standardized according to the case mix of men diagnosed from 2017 to 2020 by adjusting for age, PSA, Gleason score, clinical T stage, mode of cancer detection, primary treatment, and comorbidity by use of DCI and MDCI.Adjusted annual survival was estimated similarly, standardized according to the case mix of men diagnosed in 2020, and the 10-year survival trend was estimated after 2022 for men diagnosed between 2013 and 2020.To estimate the magnitude of difference in survival between the 3 calendar periods and annually, we calculated the restricted mean survival at 5 and 10 years. 21,22Model fit was assessed by comparing the parametric survival curves with the corresponding Kaplan-Meier curves.
Missing data for PSA, T stage, Gleason score, primary treatment, and mode of detection was imputed (5 times) using multiple imputation. 23Confidence intervals were computed by use of bootstrapping (500 resamplings) followed by multiple imputation with the boot multiple imputation percentile method. 24Statistical analyses were performed with R version 3.5.3(R Foundation).

Baseline Characteristics
Age ng/mL from 2017 to 2020.In men aged 75 to 79 years, median PSA decreased from 125 ng/mL to 58 ng/mL, and for men 80 years or older from 200 ng/mL to 116 ng/mL, whereas virtually no change was observed for men 74 years or younger (eFigure 1 in Supplement 1).Among men diagnosed with de novo metastatic disease, there were only minor changes in use of imaging techniques during the study period (eTable 1 in Supplement 1).
The parametric survival models fitted the observed survival data described by the Kaplan-Meier curves well (eFigure 2 and eTable 2 in Supplement 1).Cause-specific survival mirrored the overall survival, and the temporal trends were similar.
4.5-4.8)years for men diagnosed in 2020.The estimated survival increase was lower in men older than 80 years.

Discussion
In this nationwide population-based study in Sweden, the addition of ARPi or docetaxel to standard ADT increased substantially between 2017 and 2020.In 2020, approximately 50% of patients with de novo mCSPC received doublet therapy.Between 2008 and 2020, mean survival increased with 6 months after 5 years of follow-up in all individuals with de novo mCSPC, taking changes in age, comorbidity, and cancer characteristics into account, supporting that doublet therapy is effective in clinical practice on a population basis.

Standardization, Parametric Modeling, and Survival Estimation
Flexible parametric survival models were used to analyze survival, standardizing for changes in baseline characteristics during the study period and estimating long-term survival after 2022.The parametric gamma survival model allowed for nonproportional hazards that were expected since heterogeneous treatment intensity over calendar periods would affect survival only after around 6 Overall survival was estimated using a flexible parametric model standardized for baseline clinical characteristics according to last calendar period (2017-2020).Five-year restricted mean survival (RMS) was used to describe the increase in survival time.
Survival estimates and 95% CI are also reported in eTable 1 in Supplement 1. Numbers at risk were extracted from the unadjusted analysis.months from start of treatment. 20Restricted mean survival is a useful measure to summarize changes in survival since it accounts for shape of the entire survival curve during follow-up in contrast to median survival that represents a snapshot of the survival at the time when 50% of men have died.The increase in restricted mean survival is likely a conservative estimate of the improvement in long-term survival since we expect the time period-specific survival curves to remain separated during most of the remaining follow-up.Nevertheless, our estimation of survival beyond the observed follow-up should be interpreted with caution particularly since it does not account for future changes in treatment that are likely to increase survival even further in individuals with mCSPC.

Reasons for Improvement in Survival
In parallel to the introduction of doublet therapy, there continued to be a decrease in metastatic burden, mirrored by lower levels of PSA in individuals with mCSPC.This may partly explain the survival improvement in the last study period; however, the improvement remained after standardization for changes in cancer characteristics, including PSA levels.Furthermore, the biggest decrease in median PSA was observed among the oldest men for whom survival increased less than for the youngest men who received doublet therapy more often but whose median PSA did not decrease.There were minimal changes in the use of imaging during the study period, although there was a rise in prostate-specific membrane antigen PET use in the final year.Further studies are needed  to determine the impact on survival of more sensitive imaging modalities, such as magnetic resonance imaging and prostate-specific membrane antigen PET. 25,26

Comparisons With RCTs
8][29][30] To avoid this selection bias, we assessed survival in all men with de novo mCSPC, ie, including men who did not receive doublet therapy.9]31 In the STAMPEDE trial, the 5-year overall survival was 60% in individuals undergoing ADT plus ARPi compared with 41% in individuals undergoing ADT only, 32 whereas in our study, 5-year overall survival was 50% in men younger than 74 years in the latest calendar period, which seems reasonable given that about half of these men received doublet therapy.Men in our study population had comparable median PSA as men in the STAMPEDE trial (103 ng/mL vs 97 ng/mL), suggesting that the disease burden was quite similar. 5,33

Strengths and Limitations
This There are also some limitations to our study.Although there were no substantial changes in the diagnostic workup, eg, imaging, unmeasured and unknown changes over calendar time may have affected survival.For example, information on the extent of bone metastases was only available from 2018, precluding us to analyze high-vs low-volume disease.Furthermore, there is no information on PSA levels during follow-up in NPCR or in any other nationwide register, so we could not assess progression-free survival.Upfront treatment with docetaxel has been captured in NPCR since March 2017; however, it was used before that date mostly among individuals with mCRPC.Use of docetaxel in patients with mCSPC was correctly registered in NPCR in 84% in an audit of 500 health care records.We did not have information on the use of docetaxel in individuals with mCRPC.However, the survival benefit of docetaxel in individuals with mCRPC is limited compared with upfront use in men with de novo mCSPC. 5,34Overall, 2% of patients were treated with both docetaxel and ARPi within the first 6 months.We do not know why both drugs were used nor do we know the date for start of docetaxel treatment.We speculate that intolerance to docetaxel made the clinician switch to an ARPi.

Conclusions
A clinically meaningful increase in long-term survival was observed in men diagnosed with de novo mCSPC between 2008 and 2020 in Sweden.We argue that the main reason for this improvement was the increased upfront use of doublet therapy, combining ADT with docetaxel or an ARPi.
Continued increase in use of doublet therapy and the introduction of triplet therapy (ADT plus docetaxel plus ARPis) 31 will likely increase survival further in men with metastatic prostate cancer.

Findings
Has the introduction of doublet therapy in individuals with de novo metastatic castration-sensitive prostate cancer been associated with changes in survival on a population basis in Sweden?In this nationwide cohort study, upfront treatment with doublet therapy among 11 382 individuals between 2008 and 2020 with de novo metastatic castration-sensitive prostate cancer increased from 1% in 2016 to 44% in 2020.Mean survival in individuals with de novo metastatic castration-sensitive prostate cancer increased 6 months during the first 5 years of follow-up.Meaning In parallel with improvements in treatment of advanced prostate cancer, a clinically meaningful increase in mean survival was observed in this study.

Figure 1 .
Figure 1.Use of Doublet Therapy in Men With De Novo Metastatic Castration-Sensitive Prostate Cancer, 2008-2020

Figure 2 .
Figure 2. Standardized 5-Year Overall Survival for Men With De Novo Metastatic Castration-Sensitive Prostate Cancer Diagnosed in 2008-2020

Figure 3 .
Figure 3. Standardized Trend for Observed and Estimated 10-Year Overall Survival in Men With De Novo Metastatic Castration-Sensitive Prostate Cancer study has several strengths.The PCBaSe captures virtually all individuals diagnosed with prostate cancer in Sweden with registration of comprehensive data of cancer characteristics at diagnosis as well as primary treatment, complete capture of filled prescriptions, and complete follow-up of mortality.Comorbidity was assessed by use of 2 new indices on comprehensive data in the Patient Registry and the Drug Registry.The recency of the data is another strength of our study, with a last date of follow-up in December 2022.