Lead4Care is an observational, open-label, multicenter study evaluating the effectiveness, tolerance, and cost-effectiveness of triple against double therapy in matched groups of mHSPC patients with high tumor burden. In addition to androgen deprivation therapy (ADT), the triple constitutes of docetaxel and novel hormonal therapy (NHT), and the double of NHT therapy in addition to ADT.

Their effectiveness is compared in terms of mortality and morbidity, which is captured by HRQoL, pain, fatigue. Potential side effects are captured by neuropathy, diarrhea, constipation, anxiety, sickness, and dyssomnia. The cost-effectiveness is evaluated within a Markov model from a societal perspective in which the main disease stages are mHSPC, mCRPC and death.

In connection with a regular visit in hospital care, prostate cancer patients who in addition to ADT will initiate double or triple therapy are offered participation in the study. If the patient consent on-line, the patient will receive 13 online surveys over a 60-month period. The surveys are sent with an interval of two months for the first six months, quarterly thereafter until two years, and thereafter yearly.

Once all participants have been recruited, the baseline data shared by healthcare personnel and patients will be enriched with registry data. This baseline and registry data involves information about the patients' historical and current health- and socioeconomic status. Thereby, Lead4Care will be able to identify comparable groups of patients on triple and double treatments by using advanced matching methods.

In order to assure an objective analysis, Lead4Care will not allow any data extraction until Lead4Care has predefined and published all details regarding the comparison. The existing protocol is then complemented with a more detailed description of the comparison groups, the hierarchy of outcomes, and the analysis methods for these outcomes.

For these treatments, the main objectives are to:

• Compare mortality and morbidity on triple and double therapy, and their relative side-effects.
• Capture patient preferences for these different treatment outcomes over time.
• Evaluate cost-effectiveness of triple versus double therapy from a societal perspective.

Comprehensive evaluation:

The treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC) is evolving rapidly and treatment guidelines often need to be made before the effectiveness of available combinations have been compared. Such is the case for the current recommendation to combine androgen deprivation therapy (ADT) with new hormonal therapy (NHT) and docetaxel (DTX). This triple therapy has not yet been directly evaluated against the alternative of ADT and NHT, i.e., the double therapy. The therapies have only been evaluated indirectly in the trials PEACE-1 and ARASENS. Lead4Care will evaluate triple against double therapy with regard to potential differences in disease progression as well as tolerance. Thereby, Lead4Care will do a comprehensive comparative effectiveness (CE) evaluation which can contribute to the pool of evidence important for future guidelines.

Observational design:

Lead4Care leaves the treatment choice to the clinicians and the patients, and uses advanced matching methods to ensure comparability between patients receiving triple- and double therapy. As the groups are expected to differ in terms of their tolerance to DTX, and the doctors valuation of tolerance differ, Lead4Care expect to be able to identify such matching groups on a subset of enrolled patients. The matched groups will be used for the CE evaluation. Patients will consequently be enrolled and followed prospectively irrespective of which therapy the clinicians will choose, and similar groups will be matched especially with regard to their tolerance to DTX as proxied by their age, comorbidity, ECOG collected within Lead4Care but also in terms of their health- and socioeconomic status (SES) in general requested from national registries. The matched groups will be as similar as expected in a randomized experiment in terms of tolerance in particular, but also in terms of health, and SES. Consequently, there is no need for randomization to ensure comparability, using this study design.

Lean observational design:

The additional data that prospective studies usually collect from healthcare, can pose an administrative burden on healthcare workers. Lead4Care has therefore invested considerable effort in developing the study design which leaves few tasks to healthcare workers, i.e., only screen the patient population and report the baseline data. Instead, Lead4Care will take responsibility for all future contact with the patients according to the study protocol. This involves supporting patients in consenting to the study and in reporting their symptoms, tolerance, and progressions in the 13 on-line questionnaires. The patients will hold a patient paper diary with such critical information that the study ask the patients to remember from healthcare visits, i.e., the date and levels for PSA:s, the date for castration resistant, and the date for next treatment. Lead4Care will therefore test a design that minimizes the burden on healthcare systems and which could remove some of the administrative barriers for CE evaluations.

Pain focus:

Recent research suggests that improved pain awareness could potentially reduce the risk of SREs and/or mortality. The rationale behind this is that pain seems to serve as an indicator of development of bone metastasis as the disease advances. Adequate disease management and properly pain control can help mitigate skeleton-related events (SRE), which, in turn, can impact mortality rates. For that reason, Lead4Care will evaluate pain differences across the treatments, and explore how these pain differences potentially can predict SRE and/or mortality.

Cost-effective care:

In Sweden, the cost for prostate cancer consumes a considerable part (12%) of our cancer related healthcare costs, which in in turn constitute 3% of the total healthcare costs. Choosing cost-effective prostate cancer treatments could consequently have a visible impact on Swedish healthcare costs. Lead4Care will therefore evaluate the triple- against the double therapy from a health-economic perspective. The additional cost for adding DTX and treating its potential complications (neurotoxicity, GI side-effects, osteoporosis etc.) will be compared against the difference in quality adjusted life years (QALY). This ratio is used within Sweden for prioritization of scarce resources. Lead4Care can therefore serve as a model for the health-economic (HE) evaluations, which becomes increasingly important as the availability of prostate cancer treatments is increasing.

Patient-centered care:

In healthcare, there is often a dilemma since treatments for prostate cancer can provide survival benefits for the patients but at potential HRQoL loss. For instance, patients who undergo surgery improve their survival but their HRQoL may worsen because of complications. Moreover, patients who receive DTX in the triple therapy may improve their survival but their HRQoL may worsen because of side-effects. Lead4Care has therefore developed an instrument together with patients which captures patients treatment preferences. This instrument will ascertain patients' preferences for life prolonging or HRQoL improving treatments. Lead4Care will therefore help us better understand the populations treatment preferences. This information is important in order to better take the patients preferences into account in planning their care, just as is required in the Swedish Patient Act.

Objectives:

With the implementation of Lead4Care, the hope is to achieve the following objectives:

To evaluate the clinical effectiveness of triple- versus double therapy in matched groups of mHSPC patients with high tumour burden.

To evaluate the tolerance of triple- versus double therapy in matched groups of mHSPC patients with high tumour burden.

To describe the patients treatment preferences (gain in survival against loss of HRQoL) for mHSPC patients with high tumour burden.

To describe the cost-effectiveness of adding DTX for mHSPC-patients with high tumour burden.

To evaluate the clinical effectiveness of triple- versus double therapy in matched sub-groups of mHSPC patients with high tumour burden (e,g, w/wo visceral metastases).

To explore the way pain proxy for or predict SRE and survival for mHSPC-patients with high tumour burden with baseline bone metastases.

Inclusion Criteria:

Patients eligible for inclusion in this study must meet all of the following criteria:

• Patients should have initiated triple or double therapy no longer than 3 months from the start of ADT,
• Patients must have mHSPC at the time of enrolment, and high metastatic burden.
• Patients must be ≥ 18 years old at the time of enrolment. Note: NHT could be abiraterone acetate, apalutamide, darolutamide or enzalutamide.

Exclusion Criteria:

Participants meeting any of the of the following criteria are not eligible for inclusion:

• Patients who do not understand written and/or oral instructions in Swedish.

Patients with mHSPC and high tumor burden initiating treatment with triple or double therapy.