Real-World Treatment Trends Among Patients with Metastatic Castration-Sensitive Prostate Cancer: Results from an International Study

Abstract Background Continuous androgen deprivation therapy ± first-generation non-steroidal antiandrogen was previously the standard-of-care for patients with metastatic castration-sensitive prostate cancer (mCSPC). Treatment intensification with novel hormonal therapy (NHT) or taxane chemotherapy is now approved and guideline-recommended for these patients. Methods Physician-reported data on adult patients with mCSPC from the Adelphi Prostate Cancer Disease Specific Programme were analyzed descriptively. We evaluated real-world treatment trends for patients with mCSPC in 5 European countries (United Kingdom, France, Germany, Spain, and Italy) and the United States (US), looking at differences between patients initiating treatment in 2016-2018 and in 2019-2020. We also investigated treatment trends by ethnicity and insurance status in the US. Results This study found that most patients with mCSPC do not receive treatment intensification. However, greater use of treatment intensification with NHT and taxane chemotherapy was observed in 2019-2020 than in 2016-2018 across 5 European countries. In the US, greater use of treatment intensification with NHT in 2019-2020 than in 2016-2018 was observed for all ethnicity groups and those with Medicare and commercial insurance status. Conclusions As the number of patients with mCSPC who receive treatment intensification increases, more patients who progress to metastatic castration-resistant prostate cancer (mCRPC) will have been exposed to intensified treatments. Treatment options for patients with mCSPC and mCRPC overlap, suggesting that an unmet need will emerge for new therapies. Further studies are needed to understand optimal treatment sequencing in mCSPC and mCRPC.

The objective of our study was to evaluate real-world mCSPC treatment trends from 2016 to 2020 across a large, diverse patient population in 5 European countries (United Kingdom [UK], France, Germany, Spain, and Italy) and the US.We also investigated whether treatment trends vary by ethnicity and insurance status in the US.Our recent time period allows us to capture treatment trends after the approval of NHTs for use in mCSPC.

Study Design
Data from the Adelphi Prostate Cancer Disease Specific Programme (DSP) were utilized and subsequently analyzed for the purpose of this study.The DSP is a point-in-time, physician-conducted extraction of medical chart data.The surveys are conducted in routine clinical practice and the data collected describe patient demographics and clinical characteristics, prostate cancer disease management including treatment history, the burden and impact of prostate cancer, and associated treatment effects from the perspective of the physician.][53] Physicians in the UK, France, Germany, Spain, Italy, and the US reported information for their patients with metastatic prostate cancer attending a physician's appointment between January and August 2020.

Participants
A geographically diverse sample of physicians was identified by local fieldwork agents using physician panels and publicly available lists.All physicians self-identified as oncologists or urologists (or prostate/specialist cancer surgeons, who were included as urologists).All physicians had personal responsibility for prescribing decisions for patients with prostate cancer and were seeing 2 or more patients with mCSPC and 2 or more patients with mCRPC per month.

Patient Inclusion Criteria
At the time of data collection, patients included in this study were males aged ≥18 years, currently diagnosed with metastatic prostate cancer, not known to have ever enrolled in a prostate cancer clinical trial, and were receiving treatment for metastatic prostate cancer (any line).The data we analyzed included patients with mCSPC at the time of data collection or who had mCSPC previously and progressed to metastatic castration-resistant prostate cancer (mCRPC).All patients who initiated an mCSPC treatment between 2016 and 2020 were included in the study.
In the real-world setting, treatment intensification may include agents that are not currently approved for use in mCSPC.For the purposes of this study, treatment intensification is therefore defined as any other systemic therapy in addition to ADT, including NHT, taxane chemotherapy, taxane-based combinations, and other regimens such as radiotherapy and immunotherapy, regardless of the treatment's indication or approval status.NHTs included abiraterone, apalutamide, darolutamide, and enzalutamide.Taxane chemotherapy included docetaxel, cabazitaxel, and paclitaxel.

Physician-Reported Data
Participating physicians completed an attitudinal survey with questions on physician and practice characteristics.Following this, physicians completed detailed electronic patient record forms (ePRFs) for their next eligible, adult patients treated for mCSPC (4 patients) or mCRPC (4 patients).The number of patients per physician was limited to allow for a varied representation.
The ePRFs collected detailed information on patient demographics and clinical characteristics, patient management, and treatment history at the time of data collection.Information was collected on patients with mCSPC at data collection as well as patients with mCRPC at data collection who had historical mCSPC treatment information available.Ethnicity was identified by physicians and was not self-identified by patients.
The Eastern Cooperative Oncology Group Performance Status Scale (ECOG) was used to assess performance status, which scores from 0 (fully active) to 4 (completely disabled). 54

Ethics
The Adelphi DSP was submitted to and obtained exemption from the Western Institutional Review Board, study protocol number AG8741.
Data collection was undertaken in line with European Pharmaceutical Marketing Research Association guidelines 55 and as such it did not require ethics committee approval.Each survey was performed in full accordance with relevant legislation at the time of data collection, including the US Health Insurance Portability and Accountability Act 1996, 56 and the Health Information Technology for Economic and Clinical Health Act. 57Data were collected in such a way that patients and physicians could not be identified directly.

Analysis
Data were analyzed descriptively using IBM SPSS Data Collection Survey Reporter Version 6 or later (International Business Machines Corp., New York, USA).For continuous variables, we reported mean and SD, and/or median and range.For categorical variables, frequency and percentage distribution were reported.
Treatments initiated across all lines of mCSPC therapy in each country were reported based on year of treatment initiation and split into 2 time periods: 2016-2018 and 2019-2020.Our analysis looked at the differences between the 2 time periods.While patients appeared in each time period only once, patients could initiate multiple lines of therapy within each time period.This resulted in some answers totaling more than 100% if different options were chosen across treatment lines.
Time to treatment intensification was calculated only among patients who received treatment intensification in mCSPC and was measured both from the date of mCSPC diagnosis to the initiation of treatment intensification and from the time of first-line mCSPC treatment initiation to the initiation of treatment intensification.

Patient Characteristics
Across all countries, 328 physicians (278 in Europe and 50 in the US) provided data on 1560 patients (1321 in Europe and 239 in the US) with mCSPC (Tables 1 and 2).This included patients with mCSPC at the time of data collection and patients with mCRPC at the time of data collection who had historical mCSPC treatment information available.
Across the 5 European countries, at the time of mCSPC diagnosis, the median (range) age was 70 (44-88) years.Most patients (83%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at the time of mCSPC diagnosis.Ninety-three percent of patients were White/ Caucasian, 3% were Afro-Caribbean, and 4% were other ethnicities.At the time of data collection, the median (range) age was 72 (45-90) years.Eighty-eight percent of patients had bone metastases and 19% of patients had visceral metastases.Most patients (84%) were treated by an oncologist and 16% were treated by a urologist (including prostate/specialist cancer surgeons).Overall, just under half (47%) of patients were treated at a community hospital and just over half (53%) were treated at an academic medical center.In Germany and Italy, most patients (81% and 64%, respectively) were treated at a community hospital.However, in the UK, France, and Spain, most patients (78%, 57%, and 86%, respectively) were treated at an academic medical center (Supplementary Tables S1A and S1B).
In the US, at the time of mCSPC diagnosis, the median (range) age was 68 (49-89) years.Most patients (88%) had an ECOG performance status of 0 or 1. Sixty-seven percent of US patients were White/Caucasian, 21% were African American, and 13% were other ethnicities (including Hispanic/Latino, Asian, Middle Eastern, and mixed race).Fifty-one percent of US patients were in the Northeast.At the time of data collection, the median (range) age was 69 (50-90) years.Sixty-nine percent of patients had bone metastases and 30% of patients had visceral metastases.Three-quarters (75%) of patients were treated by a medical oncologist and the remaining quarter (25%) was treated by a urologist.Just over half (52%) of patients were treated at a community hospital and just under half (48%) were treated at an academic medical center.In total, 58% of US patients had Medicare insurance, 33% commercial, 6% Medicaid, and 3% other/no health insurance.A greater percentage of African American patients had Medicare insurance (69%) than White/Caucasian patients or patients of other ethnicity (both 55%), as well as other/no health insurance (8%, 1%, and 3%, for African American, White/Caucasian, and other ethnicity groups, respectively).A smaller percentage of African American patients had commercial insurance (14%) than White/Caucasian patients or patients of other ethnicity (39% and 29%, respectively).A smaller percentage of White/Caucasian patients had Medicaid (4%) than African American patients or patients of other ethnicity (8% and 13%, respectively; Supplementary Table S2).

Treatment Trends Across 5 European Countries by Year of Initiation
Across the 5 European countries (UK, France, Germany, Spain, and Italy), greater use of treatment intensification (NHT and taxane chemotherapy) for patients with mCSPC was observed in 2019-2020 than in 2016-2018.Germany saw the largest change in the use of treatment intensification and Italy saw the smallest change.The greatest overall use of treatment intensification in 2019-2020 was seen in Spain, with 29% of patients receiving taxane chemotherapy, 29% receiving abiraterone, and 11% receiving enzalutamide.In the UK, treatment intensification with enzalutamide was seen more than treatment intensification with abiraterone.In France, Germany, Spain, and Italy, treatment intensification with abiraterone was seen more than treatment intensification with enzalutamide.The UK had the highest percentage of patients who received treatment intensification with taxane chemotherapy relative to France, Germany, Spain, and Italy (Fig. 1A-1E).

Treatment Trends in the US by Year of Initiation
In the US, the use of treatment intensification with enzalutamide was 14% and with abiraterone was 10% in 2016-2018.In 2019-2020 the use of treatment intensification with abiraterone was 21%, 19% with enzalutamide, 7% with apalutamide, and 2% with darolutamide.Treatment intensification with taxane chemotherapy was 16% in 2016-2018 and 10% in 2019-2020.Treatment intensification with other agents was 19% in 2016-2018 and 5% in 2019-2020 (Fig. 2).Similar patterns to this were seen for White/Caucasian and African American patients, but greater use of taxane chemotherapy was observed in 2019-2020 than in 2016-2018 for patients of other ethnicities (Supplementary Table S3).When looking at treatment trends by insurance status, more NHT use and less taxane chemotherapy use was observed in 2019-2020 than in 2016-2018 for patients with Medicare and commercial insurance (Supplementary Table S4).

Treatment Trends Across 5 European Countries and the US by Physician Specialty and Disease Characteristics
In Europe, treatment intensification with a NHT, taxane chemotherapy, or both was 46% for urologist-treated patients and 45% for oncologist-treated patients.In the US, treatment intensification with a NHT was 68% for oncologist-treated  patients and 35% for urologist-treated patients (Supplementary Table S5).Disease characteristics across treatment trends are available in Supplementary Table S6.
The period from which our data are drawn overlapped with the COVID-19 pandemic, which likely had an impact on treatment trends.For context, a global survey of 129 healthcare professionals across 17 different countries (including the UK, Spain, and the US) found that 60% of institutions cancelled or postponed systemic anti-cancer therapy for oncology patients due to reasons related to the pandemic (including risk-benefit balance and insufficient staff, capacity, or resources). 59All institutions in this study implemented some changes in the delivery of treatment, including 45% of institutions that reported switching patients to oral therapies.In the US, we observed less taxane chemotherapy use and more NHT use in 2019-2020 than in 2016-2018, although in Europe, we observed more taxane chemotherapy and NHT use in 2019-2020 than in 2016-2018.One might speculate that, without the pandemic's influence, more patients would have received taxane chemotherapy relative to oral treatments such as NHT.
There is some real-world evidence on racial disparities in metastatic prostate cancer in the US that suggests treatment underutilization is of greater concern for Black than White patients. 41,60,61In contrast, our study of mCSPC patients in the US found that treatment trends appeared largely similar across ethnicities; more treatment intensification with NHT was observed for all ethnicity groups in the later time period than in the earlier time period.Additionally, although use of ADT ± first-generation NSAA (ie, no treatment intensification), was observed as lower in 2019-2020 than in 2016-2018 for the overall population as well as in African American and other ethnicity patient groups, greater use of this treatment regimen for White/Caucasian patients was observed in 2019-2020 than in 2016-2018.In a US, multi-institutional, retrospective analysis of 107 Black patients with mCSPC (of whom 87% were diagnosed with stage 4 disease in or after 2015), 27% received ADT ± first-generation NSAA and 73% received treatment intensification inclusive of 20% ADT + chemotherapy, 45% ADT + NHT, and 8% ADT + chemotherapy + NHT. 62Our analysis of US African American patients found similar treatment trends.However, our numbers of patients by US ethnicity were small, so the value of any observations of treatment patterns by ethnicity is limited.Future studies with larger sample sizes across ethnicities should further explore differences in treatment trends.
Our study also investigated how US insurance status affects real-world treatment trends.We found that, while less use of ADT ± first-generation NSAA (ie, no treatment intensification) was observed overall and in patients with Medicare in 2019-2020 than in 2016-2018, greater use of this regimen was observed in 2019-2020 than in 2016-2018 for patients with commercial insurance.The numbers of patients with Medicaid and other/no health insurance were too small to assess.
When looking at the entire study period, treatment intensification rates in Europe appeared similar across physician specialties.However, we observed more treatment intensification overall in oncologist-treated patients than in urologist-treated patients in the US, with no urologists in this study prescribing taxane chemotherapy for their patients with mCSPC.
It is important to recognize that physicians are not the only decision-makers responsible for treatment utilization.Patient preferences based on aspects of their quality-of-life, treatment accessibility, and medical expenses impact the treatments they receive. 48,63In a US survey of 100 patients with metastatic prostate cancer, 54% agreed with the statement "Avoiding financial trouble due to treatment of my prostate cancer is very important to me." 48Twenty-one percent of respondents did not agree with the statement "I rely on my doctor to tell me how to treat my prostate cancer." 48A US claims database analysis of commercially insured patients with mCRPC who received treatment intensification found that patients with a low household income were, paradoxically, more likely to receive a more expensive treatment (ie, a NHT). 63The authors concluded that qualification for patient assistance programs and thus being shielded from higher out-of-pocket costs may have been a factor in this.

Limitations
Physician selection in the DSP is a potential bias as it is influenced by willingness to take part and may not be representative of the overall population of physicians treating prostate cancer.Selection also excluded US physicians working at sites such as the Veterans Health Administration, and therefore these patients were not included in this study.Another limitation results from the fact that patients with more frequent visits are more likely to be included in the sample than patients with less frequent visits to their physician.These patients may therefore not fully represent the overall population of patients with mCSPC.However, the systematic approach to recruitment intends to reduce selection bias.
Although the overall sample size for this study was large, sample sizes per country were small; future studies with larger sample sizes per country should investigate this topic further.Additionally, reimbursement for different medications varies widely by country and will therefore influence the treatment trends of each country studied.Reimbursement in European countries may vary by regions within countries; however, this level of analysis was not possible.
Sample size also meant that we were unable to analyze more granular, annual treatment trends; thus, we chose the 2016-2018 and 2019-2020 time periods presented in this study.To be selected for this study, patients with mCSPC during 2016-2018 had to continue medical visits with their physician until 2020, which may have led to differences in baseline characteristics between the 2 time periods.Additionally, sample size is not the same for all patient baseline demographics and disease characteristics.This is because the DSP allowed physicians to state "don't know" in response to some questions so as not to limit collection.
Our study used descriptive analyses only and we were therefore unable to make conclusions based on comparisons between any patient groups or between the 2 study periods.

Conclusions
This study found that most patients with mCSPC do not receive treatment intensification despite the availability of these therapies.However, we observed greater use of treatment intensification with both NHT and taxane chemotherapy in 2019-2020 than in 2016-2018 across 5 European countries.In the US, more treatment intensification with NHT was observed for all ethnicity groups, as well as those with Medicare and commercial insurance status, in 2019-2020 than in 2016-2018.
As the number of patients with mCSPC who receive treatment intensification increases and time to treatment intensification decreases, more patients who progress to mCRPC will have been exposed to intensified treatments.As therapies for patients with mCSPC and mCRPC overlap, patients who progress to mCRPC may need new treatment options.This suggests an unmet need will emerge for new therapies in mCRPC and highlights the need for further studies to understand optimal treatment sequencing in mCSPC and mCRPC.
to treatment intensification was calculated only among patients who received treatment intensification in mCSPC, and was measured both from the date of mCSPC diagnosis to the initiation of treatment intensification and from the time of first-line mCSPC treatment initiation to the initiation of treatment intensification.a Includes 5 European countries only: UK, France, Germany, Spain, and Italy.Abbreviation: mCSPC, metastatic castration-sensitive prostate cancer; UK, United Kingdom; US, United States.

Table 1 .
Patient baseline demographics in 5 European countries and the US.
a Includes 5 European countries only: UK, France, Germany, Spain, and Italy.b Clinical oncologist is a UK-specific specialty covering both medical and radiation specialties.c Urologist includes 7 physicians in Spain who selected "Prostate/specialist cancer surgeon.".d Afro-Caribbean in Europe; African American in US. e States within each geographic region:.

Table 2 .
Patient baseline disease characteristics in 5 European countries and the US.

Table 3 .
Time to mCSPC treatment intensification by year of mCSPC treatment initiation.