Rehabilitation intervention to prevent adverse events related to ADT in patients with metastatic prostate cancer

Abstract

In patients with prostate cancer (PCa), androgen deprivation therapy (ADT) is associated with multiple side effects, including increased fat mass (FM), loss of muscle mass and strength, osteoporosis, risk of falls, disability, fatigue, and a decline in quality of life (QoL). Multicomponent exercise programs have been shown to mitigate several of these adverse events.

Preliminary evidence suggests that exercise can be safely implemented in patients with metastatic PCa and that physical inactivity should be avoided, even in advanced stages. However, studies involving this fragile population remain limited.

This single-arm interventional study aims to evaluate the feasibility and safety of an exercise-based rehabilitation program in hormone-sensitive patients undergoing ADT, alone or combined with other therapies.

HIGHLIGHTS

Prostate cancer treatment overview

• In recent years, patients with metastatic prostate cancer have experienced longer survival rates, but they have also faced treatment-related adverse events that can compromise both quality of life and life expectancy.

• The extended survival has resulted in prolonged exposure to androgen deprivation therapy (ADT), which is associated with adverse events such as muscle weakness, fatigue, osteoporosis, and an increased risk of falls and fractures.

• While exercise has the potential to mitigate these adverse events, concerns about its safety in an elderly population, particularly those with bone metastases, have limited its widespread application.

• However, exercise guidelines for cancer survivors recommend that cancer patients, including those with bone metastases, should avoid physical inactivity.

ReCaP trial design

• The ReCaP trial is a drug-free single-arm single-center interventional study investigating the feasibility of a tailored exercise program for metastatic prostate cancer (PCa) patients undergoing androgen deprivation therapy (ADT).

• Eligible patients are adult men (≥18 years) with a diagnosis of metastatic PCa and an ECOG Performance Status (PS) of 0–1 who are candidates for ADT alone or in combination with other treatments. Patients with physical or psychological/psychiatric conditions that may limit adherence to the study, or those with other active malignancies, will be excluded.

• The following data will be collected upon baseline assessment: sociodemographic data, anthropometric data, ECOG PS and medical history, including, bone lesions, pain, risk of pathological fractures, muscle strength, physical performance, level of fatigue, and level of habitual physical activity.

• Enrolled participants will be invited to participate in a 12-week rehabilitation program, starting within 3 months of initiating ADT. The intervention consists of a multicomponent tailored exercise program (including aerobic, resistance, and balance exercises) performed thrice weekly, with 2 supervised and 1 home-based session.

• Outcomes will be assessed at baseline (T0), at the end of the intervention (T1), and at follow-up, which will occur 24 weeks and 12 months from baseline (T2 and T3).

• A total of 38 participants will be enrolled, with a 20-month accrual period.

ReCaP trial endpoints

• Primary outcome will be the feasibility of the rehabilitation intervention measured by adherence, defined as percentage of participants who complete treatment schedule ≥ 75% after 12 weeks.

• Secondary outcomes will be: recruitment rate and retention rates, safety, upper limbs muscle strength, physical performance, level of fatigue, habitual physical activity level.

• Secondary outcomes will be measured at baseline, after 12 weeks, 24 weeks and 12 months.

1. Introduction

1.1. Background and rationale

Recent research has provided strong evidence supporting the role of exercise in improving the tolerance to various side effects of cancer therapies, such as fatigue, anxiety, depression, physical function, sleep disturbances, and bone health. Exercise has also been shown to improve quality of life and even survival in some cancer types [1,2]. While international guidelines offer general recommendations on physical activity, there is growing awareness among patients of the benefits a healthy lifestyle can provide during their cancer treatment. Cancer patients prefer receiving information about physical activity from their oncology providers [3]. However, several oncologists remain hesitant to prescribe exercise to these patients, often due to concerns about their ability to tolerate and sustain it over time [4].

Exercise is especially crucial for patients with metastatic prostate cancer (PCa). Recent advances in therapy, particularly the combination of ADT with androgen receptor pathway inhibitors (ARPIs), and in selected cases, with ARPIs and Docetaxel during the hormone-sensitive stage, have significantly improved survival rates in these patients [5–9]. However, prolonged exposure to ADT is associated with several adverse events (AEs) that may compromise both quality of life and overall life expectancy.

While the addition of ARPIs to ADT has demonstrated benefits in preserving—or even improving—specific QoL parameters such as general health status and pain control, these regimens are also associated with a potential increase in ADT-related AEs. Furthermore, heterogeneity in QoL assessment tools and time points across studies hinder reliable comparisons and limit the generalizability of results [10]. These AEs include erectile dysfunction (ED), muscle weakness, fatigue, osteoporosis, and an increased risk of falls and fractures [11].

Over the past decades, significant efforts have been made to mitigate the adverse effects related to sexual dysfunction. Recently, increased focus on ED management in metastatic prostate cancer has emerged, supported by a growing range of pharmacological treatments tailored to patients’ needs, comorbidities, and ED causes (e.g., hormone therapy, surgery, radiotherapy). Multimodal approaches are often recommended to optimize outcomes [12].

Concerning musculoskeletal toxicities, since prostate cancer predominantly affects older men, these side effects are often compounded by age-related loss of muscle mass [13]. Actually, these side effects arise due to changes in body composition, as testosterone plays a key role in lipolysis and in maintenance of lean muscle mass (LM). For instance, within the first 9 months of ADT, patients with PCa experience a 13.8% increase in fat mass (FM) and a 2.4% decrease in LM, which significantly raises the risk of obesity and sarcopenic obesity—conditions linked to higher mortality [14].

The decline in LM in patients with PCa also leads to reduced muscle strength and worsens performance on physical function tests compared to both untreated PCa survivors and age-matched men without cancer. Low muscle strength is associated with self-reported functional limitations and an increased risk of both current and future disabilities [15]. Moreover, reduced LM is linked to a higher incidence of falls [14]. Men undergoing ADT are more than twice as likely to experience falls compared to those not on ADT (37 vs. 15%), facing higher risks of fractures, hospitalization, and disability, which profoundly impact their quality of life (QoL). Older individuals with disabilities tend to have more complex care needs, are more likely to be admitted to long-term care facilities and are at a greater risk of mortality than those who remain independent [16]. Combination therapy with ARPIs and ADT is also linked to higher rates of musculoskeletal AEs such as falls and fractures. In the TITAN trial, apalutamide plus ADT led to more falls (7.6 vs. 5.2%) and fractures (11.7 vs. 6.5%) than placebo [7], and enzalutamide showed similar risks in the ARCHES trial [17]. Fatigue is another frequent adverse event; for example, 47% of patients on enzalutamide plus ADT reported fatigue versus 25% with standard care in ENZAMET [6]. Moreover, in patients receiving triplet therapy, taxane-induced peripheral neurotoxicity may confound the evaluation of musculoskeletal toxicity in metastatic hormone-sensitive prostate cancer patients, as overlapping symptoms (e.g., neuropathic pain vs myalgia/arthralgia) [18]. These results highlight the need for careful bone health monitoring, preventive measures, and tailored management in patients receiving hormone-based treatment.

Adopting a healthy lifestyle that combines proper diet and regular exercise has proven effective in improving the FM/LM ratio in the general population. In patients with prostate cancer, research conducted over the last 20 years has shown that combined aerobic and resistance exercise reduces FM, improves muscle strength and cardiovascular function, and seems to positively impact QoL [19].

However, few studies have focused specifically on patients with metastatic PCa, likely due to concerns about age and bone metastases, which increase the risk of skeletal fractures, spinal compression, and bone pain. Preliminary data suggest that, with careful planning, exercise can be safely incorporated into the treatment of this population [20]. Exercise guidelines for cancer survivors recommend that cancer patients, including those with bone metastases, should avoid physical inactivity [21,22].

Recent research has also highlighted that muscle mass is inversely associated with cancer-related fatigue. Two studies involving advanced cancer patients showed lower fatigue scores in men with higher skeletal muscle mass [23,24]. Clinically relevant fatigue is a common issue for PCa patients undergoing ADT, becoming more prevalent within the first 6 months of treatment and plateauing around 12 months [25,26]. A study by Storey et al. found that 43% of patients with a median ADT treatment duration of 22 months reported clinically significant fatigue [27].

Several studies have demonstrated that resistance exercise [28] or a combination of resistance and aerobic exercise [29–31] can significantly improve fatigue in PCa patients undergoing ADT.

Based on these findings, we hypothesize that a tailored exercise program, recommended by cancer care providers and delivered by qualified exercise professionals, could be both feasible and beneficial to patients with metastatic PCa undergoing ADT, even in the presence of bone metastases. Additionally, we aim to assess whether the program can lead to lifestyle changes over a 12-month period.

1.2. Objectives

The main aim of the current study is to assess the feasibility of a tailored exercise program, measured by adherence to exercise program, in metastatic PCa patients undergoing ADT.

Secondary aims are to deepen the knowledge of other feasibility aspects (recruitment/retention), to monitor safety, to assess the effects on reducing the AEs of ADT (loss of strength, loss of physical performance and fatigue, number of accidental falls and fractures), and to monitor pain and changes in physical activity habits.

2. Methods

2.1. Trial design, inclusion criteria and participant timeline

This is a drug-free single-arm single-center feasibility interventional study. The Institutional Review Board (Comitato Etico Area Vasta Emilia Nord—AVEN) approved the trial on 16/05/2023. This study protocol was prospectively registered on ClinicalTrials.gov with the Identifier NCT06238596 and adheres to the recommendation of SPIRIT guidelines for reporting in clinical trials [32]. The study is conducted at the Local Health Authority of Azienda USL-IRCCS of Reggio Emilia, in northern Italy. Eligible patients are adult men (≥ 18 years) with a diagnosis of metastatic PCa who are candidates to receive ADT alone or in association with other treatments. Permitted treatments are limited to those currently approved in Italy, including combinations of androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPI) such as abiraterone, enzalutamide, or apalutamide, as well as triplet therapy with ADT, ARPI, and docetaxel. The use of radiotherapy to the primary tumor and to metastatic sites is also permitted when clinically indicated. Further inclusion criterion is Eastern Cooperative Oncology Group Performance Status (ECOG PS) score 0–1 [33].

Exclusion criteria are the following:

• Physical or psychological/psychiatric conditions that may limit adherence to the study (heart failure NYHA 3–4, pathologic fractures, previous disability limiting exercise, moderate-severe cognitive impairment, psychiatric disorders, et cetera);

• Additional concomitant active malignancies.

Eligible patients will be invited to participate in a 12-week rehabilitation intervention, consisting of three sessions per week, within 3 months from ADT start (first administration of LH-RH analogue). Outcomes will be assessed at baseline (T0), at the end of the intervention (T1), and at follow-up, which will occur 24 weeks and 12 months from baseline (T2 and T3). Figure 1 represents the study flow diagram with procedures and participants’ timeline.

Figure 1.

Schematic study flow diagram.

2.2. Recruitment procedures

Eligible patients will be identified by oncologists and radiotherapists. If inclusion and exclusion criteria are met, oncologists will introduce and discuss with patients the main aspects of the trial. Furthermore, study information sheets will be provided and, if patients agree to participate, a written consent will be collected. The recruitment period is estimated to be 20 months.

2.3. Baseline assessment

At the baseline assessment the oncologist will collect sociodemographic data (age, education level, availability of caregiver), anthropometric data (weight and height), ECOG PS and medical history, including date of diagnosis of PCa, histology of cancer, previous treatment for localized disease and response to oncological treatments, number of metastatic sites, site of metastasis (pelvis, vertebrae, ribs, proximal femur and all regions), date of start of ADT, other treatments associated with ADT, comorbidities, and recent accidental falls and fractures.

Also, a physiatrist will collect data on sites of bone lesions, their associated level of pain by the numerical rating scale (NRS), and the risk of pathological fractures. Cancer-related instability of the vertebral column will be assessed by the spinal instability neoplastic score (SINS), which is a reliable tool to guide the management of patients with neoplastic spinal disease [34]. Bone metastases involving hip or femur will be analyzed according to Mirel’s score, and an orthopedic surgeon will be consulted in case of potential instability of the bone lesion [35].

A physiotherapist will collect functional data for all participants on muscle strength, physical performance, level of fatigue, and level of habitual physical activity.

Anthropometric, clinical, and functional data will also be monitored per the follow-up schedule shown in Table 1.

Table 1.

Data collected and follow-up scheduled.

Assessment and timepoint	T0 (baseline +/− 10 days)	T1 (12 weeks +/− 10 days)	T2 (24 weeks +/− 10 days)	T3 (12 months +/− 10 days)
ICF sign	X
Oncology or radiotherapy visit	X			X
Enrollment	X
Socio-demographic data	X
Height and weight	X	X	X	X
Medical history	X
Clinical data (ECOG-PS, comorbidities and therapies, falls and fractures, bone pain, response to oncological treatments)	X	X	X	X
Physiatrist visit	x
Physiotherapy clinical assessment
HGS	X	X	X	X
SPPB	X	X	X	X
FACIT-Fatigue scale	X	X	X	X
IPAQ-SF	X	X	X	X
Experimental treatment	←-----------------------------------➔
Feasibility and safety assessment
Recruitment rate	X
Retention rate	X	X	X	X
Adherence rate	X	X
AEs related and not related to intervention	X	X	X	X

Abbreviations: ICF: informed consent form; ECOG-PS: Eastern Cooperative Oncology Group Performance Status; HGS: Hand Grip Strength; SPPB: Short Physical Performance Battery; FACIT-Fatigue Scale: Functional Assessment of Chronic Illness Therapy - Fatigue Scale; IPAQ-SF: International Physical Activity Questionnaire—Short Form; AEs: adverse events.

2.4. Rehabilitation intervention

The rehabilitation intervention consists of a thrice-weekly individually tailored multicomponent exercise program for 12 weeks. Two sessions per week will be supervised by a physiotherapist in person or by online videoconference, as preferred by participants. In-person sessions will be conducted in small groups (up to 6) or individually at the Physical Medicine and Rehabilitation Unit of Santa Maria Nuova Hospital of Reggio Emilia, according to scheduled appointments. Furthermore, participants will be recommended and educated on how to perform a third weekly unsupervised session at home.

The physiotherapist will provide an exercise booklet with pictures, video, and explanations of the exercises performed during the supervised sessions to maximize accuracy of the unsupervised execution by participants and to support long-term home-based exercise.

Overall, the dose of the 12-week individually tailored multicomponent exercise program adheres to the recommendation of the guidelines for cancer survivors [1,36].

At the end of the 12 weeks, the physiotherapist will recommend carrying on performing the exercise program in the home-based setting, using the tailored booklet.

The multicomponent exercise program includes aerobic, resistance, and balance exercises, according with the exercise guidelines for cancer survivors [1]. In addition, impact-loading exercises are provided only for participants without bone metastasis to avoid direct loading on the metastatic lesions, according to the recent evidence [20,37]. This type of exercise has been applied in patients with PCa receiving ADT to prevent the loss of bone mineral density [38].

Sessions will last approximately 60 minutes and will be organized as follows: a 10-minute warm-up, 20–30 minutes of aerobic exercise, and 30 minutes of resistance, balance, and (if indicated) impact-loading exercises. The session will conclude with a 5-minute cool-down period of light aerobic activities (walking, stationary bike) or flexibility exercise, based on the participant’s preferences. The details of each exercise component are the following:

• Progressive aerobic exercise: 20–30 minutes of aerobic activity at moderate intensity (walking or stationary bikes), with a target intensity of 60–85% estimated maximum heart rate (% HRmax), The duration of aerobic exercise will increase from 20 to 30 minutes over 12 weeks, increasing by 5 minutes every 4 weeks.

• Progressive resistance exercise: strength activity of the major trunk, lower, and upper extremity muscle groups at a moderate intensity ranging from 8 to 15 repetitions, for 2–4 sets for each exercise. The progression of exercise intensity will change over the weeks based on the participant’s compliance and performance.

• Balance exercise: standing balance activities (e.g., stand on one leg, stand with unstable support base) and dynamic functional tasks (e.g., stop walking balanced on one foot, walking backward). Balance exercise will be associated with cognitive tasks (e.g., counting, memory/attention tasks). To provide progression, exercises will be modified by introducing difficulties (e.g., adding further cognitive or motor task).

• Impact-loading exercise (if indicated): activities that provide impact with the ground reaction force using the body weight as a load (e.g., hopping, going up and down steps, sudden changes in walk direction, acceleration/deceleration).

• Flexibility exercises: 2–3 repetitions for 30–60 seconds of static stretching for upper and lower extremity muscle groups.

To provide a large number of stimuli, several tools will be used (e.g., resistance bands, fitball, unstable supports, hurdles, soft balls, step, et cetera).

A detailed description summary of exercises, progression, and tools is provided in Table 2. The modifications of specific exercises for participants with bone metastases are guided by the location of bone lesions so that the affected sites are not targeted and that load is minimized [39]. Bone pain was monitored during each rehabilitation session to allow for individualized adjustments to the intervention, ensuring safety and tolerability.

Table 2.

Summary of exercise program and modifications for bone metastases.

Type of exercise	Duration	Exercise without BM	Exercise with BM
Aerobic exercise	20–30 min	Walking or stationary bike with a target intensity of 60-80% of HRmax.	If pelvis and/or femur BM§: stationary bike with a target intensity of 60-80% of HRmax.
Resistance exercise*	30 min	Lower and upper extremity muscle groups and postural and trunk muscles: strengthening with graduated anklets, weights, resistance bands, fitball, step.	If pelvis and/or femur BM and upper limbs BM: exercises without weight/bands/anklets are used for involved regions. If axial skeleton (lumbar, thoracic, cervical, ribs) BM: exercises without weight/bands and restricted ROM or avoided movements are used for involved regions.
Balance exercise*		Standing balance activities and dynamic functional tasks associated with cognitive tasks. Tools used include unstable support.	If pelvis, and/or femur BM§: no standing balance activities are permitted. Inclusion exercises sitting on the fitball.
Impact-loading exercise*		Hopping, going up and down steps, multidirectional movements, acceleration/deceleration. Tools used include weight, graduate anklets, hurdles, steps, training cone markers.	If pelvis, axial skeleton (lumbar,, thoracic, cervical, ribs) and/or femur BM: no impact-loading exercise is permitted.
Flexibility exercise	5 minutes	Static stretching for upper and lower extremity muscle groups.	If axial skeleton BM: exclusion of spine flexion/extension/rotation, especially when BM involves junctional and mobile spine (C1-T2; T11-L4) and patient refers pain.

Abbreviations: BM, bone metastases; HRmax: maximum heart rate; ROM: range of motion.

^§ Exercises are not permitted in patients with axial lumbar skeleton BM associated to bone pain and/or orthopedic indications of physical limitation.

^*For this type of activity, the use of circuits with different exercises performed continuously for multiple repetitions or for set times is planned.

2.5. Outcome measures

The primary outcome will be the feasibility of the rehabilitation intervention measured by adherence rate, defined as the percentage of study participants who complete a minimum of 75% of the treatment schedule [40].

Secondary outcomes include recruitment rate, retention rates, safety, upper limbs muscle strength, physical performance, level of fatigue, habitual physical activity level (Table 3).

Table 3.

Secondary outcomes.

Outcome	Description
Recruitment rate	Percentage of eligible patients who agree to participate in the study.
Safety	Monitoring of accidental falls, traumatic and pathological fractures during the study, and pain at bone metastasis sites (measured using the NRS Scale). Adverse events (AEs) related and unrelated to the rehabilitation intervention (such as pain, falls, or fractures occurring during exercise sessions) will be recorded.
Upper limbs muscle strength	Assessed using a hand grip strength (HGS) dynamometer [48], a reliable measure linked to hospital costs, all-cause mortality, and functional decline in middle-aged and older adults. Evaluations will be conducted at baseline, 12 weeks, 24 weeks, and 12 months. Strength levels will be categorized as low (<27 kg) or normal (≥27 kg).
Physical performance	Measured using the Short Physical Performance Battery (SPPB) test [49], which assesses lower limb function related to gait, balance, and strength. The SPPB is predictive of adverse outcomes such as mortality, disability, falls, hospitalization, and healthcare utilization. Evaluations will occur at baseline, 12 weeks, 24 weeks, and 12 months. Scores will be classified as low (<8) or normal (≥8).
Level of fatigue	Assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scale [50], a 13-item patient-reported outcome measure evaluating fatigue symptoms and their impact on daily functioning. Scores range from 0 (“not at all”) to 4 (“very much”), with a total score range of 0 to 52. The general population mean score is 43, with lower scores indicating greater fatigue. The minimum clinically important difference (MCID) is 3 points. Evaluations will take place at baseline, 12 weeks, 24 weeks, and 12 months.
Habitual physical activity level	Assessed using the International Physical Activity Questionnaire – Short Form (IPAQ-SF) [51], which estimates the frequency and duration of vigorous, moderate, and mild physical activity over the previous 7 days. Activity levels will be categorized as good (≥1 hour of moderate activity per day), moderate (≈30 minutes of moderate activity most days), or poor (weekly moderate activity or less). Evaluations will be conducted at baseline, 12 weeks, 24 weeks, and 12 months.

2.6. Statistical analysis

2.6.1. Sample size calculation

We dimensioned this feasibility study on the primary outcome (the percentage of adherent participants) and considering a single arm (phase-2-like) experimental study setup [41]. Accordingly, 36 evaluations will grant an 80% (beta = 20%) power to demonstrate that adherence is higher than 60% (p0, considered to be the last of unuseful treatments) in case our treatment has an adherence (p1) of 80% (delta = 20% was determined as clinically noteworthy and logistically feasible for accrual project/financing time constraints) by using a one-tailed binomial exact test (with alpha = 5%). Finally, considering also a 5% missingness on primary outcome, 38 participants are needed to be enrolled in the current study.

2.6.2. Statistical methods for primary and secondary outcomes

Analysis by outcome:

1. We will perform a one-tailed exact binomial test for feasibility proportion against the null hypothesis (p0 = 60%, alternative: unilateral, greater); a p-value below 0.05 will be considered statistically significant. Equivalently we will estimate the one-tailed 95% upper confidence interval for feasibility by the method of Clopper-Pearson and verify if the lower margin is above 0.6.

2. Following outcome order:

   1. Recruitment rate will be estimated as percentage and accompanied by a Clopper
   2. Pearson two-tailed 95% confidence interval.
   3. Retention rates at 12 and 24 weeks and at 12 months will be analyzed as outcome 2.a.
   4. Safety outcomes will be summarized by tables, listings, and descriptive statistics.
   5. Upper strength will be estimated as the percentage of participants with Hand Grip Strength (HGS) ≥27 kg on the primary hand (normal strength) at baseline and after 12 weeks and compared using McNemar’s test for paired proportions. A p-value below 0.05 will be considered statistically significant. Otherwise, strength in kg will be summarized in time by graphs and proper summary descriptive statistics.
   6. Short Physical Performance Battery (SPPB) measurements (% of participants with score ≥ 8 at baseline and after 12 weeks) will be analyzed as outcome 2.d.
   7. Functional Assessment Of Chronic Illness Therapy—Fatigue (FACIT-F) measurements mean delta estimate (12 weeks baseline) will be accompanied by a 95% confidence interval assuming an asymptotically normal distribution of the estimator. Otherwise, the outcome in time will be descriptively summarized.
   8. International Physical Activity Questionnaire Short Form (IPAQ-SF) classifications will be analyzed as contingency table against time (absolute and relative frequencies within time); to explore the association of time with IPAQ (baseline vs 12 weeks) we will compare a mixed effect ordinal model (fixed effect: time, random effect: 1 intercept per participants) with its null counterpart via likelihood ratio test.

A complete case analysis will be performed; we expect that primary outcome missingness will be negligible (<5%) and will have been accounted for in trial dimensioning.

2.6.3. Data collection management and monitoring

All data will be entered electronically. The data will be processed by an electronic Case Report Form (CRF). Azienda U.S.L.—IRCCS of Reggio Emilia will process the personal data of the subjects participating in the study as independent Data Controller and according to the realization of the study itself. In accordance with current European legislation, informed consent of participants will be collected for enrollment in the study and the processing of personal data, pursuant to GDPR 679/2016, D.Lgs. 196/2003, as amended by D.Lgs. 101/2018.

The identification data of the subject will be recorded in coded form. Personal data will be pseudo-anonymized. The identification data (name) and the corresponding alphanumeric codes will be stored in a separate “decoding” file. Only the participant code (i.e., participant ID) will be recorded in the CRF. All the information collected in the CRF will be made accessible only to collaborators authorized by the PI as data processing responsible and access to the CRF will only be possible for the staff involved in the study.

The Principal Investigator is responsible for the data monitoring. No external data monitoring committee is planned for this feasibility study. The investigators will allow site trial related monitoring, audits, Institutional Review Board/Independent Ethics Committees review and regulatory inspections of the study (both during and after its completion).

2.6.3.1. Harm and adverse event reporting

The baseline accurate assessment of participants, including identification of bone frailty and sites of metastases, helps clinicians to offer the most personalized rehabilitation intervention to each participant, respecting his/her general condition and overall frailty, if present. A different exercise program has been set up for participants with bone metastases, according to recent expert consensus recommendations [42].

Safety data will be collected in terms of the number of accidental falls and fractures, in accordance with the aim and outcomes of the present protocol. Participants may be exposed to harm related to exercise and physical activity; we will distinguish between AEs related to the exercise program (pain or falls or fractures occurring during exercise sessions) and AEs not related to exercise.

Insurance for participants is provided.

3. Ethics and dissemination

The trial will be carried out in compliance with the protocol, the ethical principles laid down in the Declaration of Helsinki, in accordance with the General Data Protection Regulation, the principles of Good Clinical Practice, and other relevant regulations. The investigator will immediately inform the Research Institution of any urgent safety measures taken to protect the trial participants against any immediate hazard. Prior to participation in the trial, written informed consent must be obtained from each participant according to ICH-GCP and to the regulatory and legal requirements of the participating country. Each signature must be personally dated by each signatory, and the informed consent form must be retained by the investigator as part of the trial records. A signed copy of the informed consent must be given to each participant.

In terms of dissemination strategy, the Trial Steering Committee aims to publish the ReCaP protocol to share with clinicians and other research groups participants’ timeline assessments and intervention description. After data analyses, the results of the study will be disseminated, preferring an open access practice to improve the accessibility and reproducibility of its outcomes.

4. Conclusion

There is growing evidence supporting the benefits of physical exercise for patients living with cancer, particularly in reducing treatment side effects, improving quality of life, and, in some cases, even enhancing survival. Cancer associations have endorsed the implementation of exercise in clinical practice, yet it remains an underutilized approach [43]. Although oncologists seem interested in the topic, data show that only one-third of patients receive advice on the benefits of exercise and the availability of facilities [44,45]. Several factors contribute to this issue, including time constraints, lack of knowledge, and concerns about the feasibility and tolerance of exercise, especially in metastatic patients [4].

The ReCaP trial aims to explore, as a primary outcome, the feasibility of a tailored exercise program for metastatic prostate cancer patients, adding rehabilitation to the standard care. In this population of cancer patients, the concerns mentioned above are intensified by older age, the predominance of bone metastases, and comorbidities. We believe that demonstrating the feasibility of a structured exercise program in this patient population may help increase healthcare professionals’ confidence in prescribing such interventions in clinical practice.

The assessment of secondary outcomes is useful to describe the effect of the intervention. Functional indicators, fatigue levels, and physical activity level provide concrete data, while the recruitment rate reflects its acceptability. Safety monitoring ensures the intervention is well tolerated and free of significant risks.

As a single-arm study, the effectiveness of the rehabilitation intervention on health outcomes cannot be determined due to the lack of a control group. Additionally, the population under study will likely be heterogeneous, since eligible patients may vary in terms of disease burden and therapies associated to ADT. For example, some study participants may be candidates for triplet therapy, which includes novel hormonal agents and chemotherapy, and/or may receive concomitant steroids if required by their treatment protocols.

Moreover, comorbidities such as metabolic syndrome [46] and other age-related conditions [47] further increase the variability within the sample and may influence both the occurrence of adverse events and the response to the rehabilitation intervention. These aspects underline the complexity of this patient population and the need for personalized approaches in supportive care.

Furthermore, excluding patients with ECOG PS >1, advanced heart failure (NYHA 3–4), pathologic fractures, and cognitive impairment may limit the generalizability of our findings to frailer patients. However, these criteria were necessary to properly evaluate the feasibility of the rehabilitation program particularly in this early phase of investigation. Future research should explore the applicability of such interventions in more vulnerable populations.

Thanks to the long term follow-up, we aim to determine whether exercise prescription over the course of a year can significantly influence participants’ lifestyles, promoting lasting improvements in their physical activity habits and overall well-being.

With these limitations in mind, the results of this study will provide us with data on the feasibility and safety of the exercise in this population, while the assessment of intervention effectiveness on secondary outcomes remains exploratory and descriptive due to the single-arm design.

If the study successfully meets its primary endpoint, future randomized controlled trials with sufficient statistical power could be designed to assess the effectiveness of a rehabilitation program integrated into cancer care.

Funding Statement

This research was funded by the Italian Ministry of Health as part of the program “5perMille, year 2021” promoted by the AUSL-IRCCS of Reggio Emilia, Italy. This study was partially supported by the Italian Ministry of Health-Ricerca Corrente Annual Program 2026.

Ethical statement

The study will be open to enrollment only after the approval of Ethics Committee and the authorization issued by General Manager of Azienda U.S.L.—IRCCS of Reggio Emilia, pursuant to L.R. 9/2017. The study protocol, each amendment, and the consent for data processing must be approved and notified to the Ethics Committee. This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study will comply with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting), with the E.U. Clinical Trial Directive (2001/20/EC) and applicable local, regional, and national laws.

Consent for publication

Informed consent is attached to the protocol.

Author contributions

SdG is the Chief Investigator; she conceived the study, led the proposal and protocol development. MA, SF, SC, LB, CP, and GC contributed to the study design and to the development of the proposal. All authors read and approved the final manuscript.

Disclosure statement

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Data availability statement

The investigator is responsible for archiving and storing the essential documents of the study before, during the conduct and after the completion or possible interruption of the study itself, in accordance with what/for the time required by current legislation. The data collected in the database will be strictly anonymous and the participant enrolled in the study will only be identified with a number. Participant’s original data (e.g., demographic and medical information) and the original signed informed consent and privacy form will be shared only with personnel authorized by the principal investigators and only for specific protocol aims. Final full dataset will be available to the trial investigators (SdG, SF, SC, MA, GC, LB, and CP).