Key Points
Question
What is the feasibility and tumor biological activity of neoadjuvant exercise therapy in men with localized prostate cancer?
Findings
In this decentralized, phase 1a, nonrandomized clinical trial that included 53 men with treatment-naive localized prostate cancer in the preoperative setting, all exercise therapy dose levels were feasible, with 225 to 375 minutes per week showing promising biological activity.
Meaning
The results of this trial suggest that 225 minutes per week can be selected as the recommended phase 2 dose; further evaluation of exercise therapy at this dose is warranted in prostate and other solid tumors.
Abstract
Importance
Observational data have shown that postdiagnosis exercise is associated with reduced risk of prostate cancer death. The feasibility and tumor biological activity of exercise therapy is not known.
Objective
To identify recommended phase 2 dose of exercise therapy for patients with prostate cancer.
Design, Setting, and Participants
This single-center, phase 1a dose-finding trial was conducted at a tertiary cancer center using a patientcentric, decentralized platform and included 53 inactive men with treatment-naive localized prostate cancer scheduled to undergo surgical resection between June 2019 and January 2023. Data were analyzed in June 2024.
Intervention
Six escalated exercise therapy dose levels ranging from 90 to 450 minutes per week of individualized, moderate-intensity treadmill walking, allocated using adaptive continual reassessment. All exercise therapy sessions were conducted remotely with real-time monitoring.
Main Outcomes and Measures
Feasibility was evaluated by relative exercise dose intensity (REDI). A dose level was considered feasible if 70% or more of patients achieved an REDI of 75% or greater. Activity end points were changes in tumor cell proliferation (Ki67) and plasma prostate-specific antigen levels between pretreatment and postintervention. Safety and changes in patient physiology were also assessed.
Results
A total of 53 men were enrolled (median [IQR] age, 61 [56-66] years). All dose levels were feasible (≥75% REDI). The mean (95% CI) changes in Ki67 were 5.0% (–4.3% to 14.0%) for 90 minutes per week, 2.4% (–1.3% to 6.2%) for 150 minutes per week, –1.3% (–5.8% to 3.3%) for 225 minutes per week, –0.2% (–4.0% to 3.7%) for 300 minutes per week, –2.6% (–9.2% to 4.1%) for 375 minutes per week, and 2.2% (−0.8% to 5.1%) for 450 minutes per week. Changes in prostate-specific antigen levels were 1.0 ng/mL (–1.8 to 3.8) for 90 minutes per week, 0.2 ng/mL (–1.1 to 1.5) for 150 minutes per week, –0.5 ng/mL (–1.2 to 0.3) for 225 minutes per week, –0.2 (–1.7 to 1.3) for 300 minutes per week, –0.7 ng/mL (–1.7 to 0.4) for 375 minutes per week, and –0.9 ng/mL (–2.4 to 0.7) for 450 minutes per week. No serious adverse events were observed. Overall, 225 minutes per week (approximately 45 minutes per treatment at 5 times weekly) was selected as the recommended phase 2 dose.
Conclusions and Relevance
The results of this nonrandomized clinical trial suggest that neoadjuvant exercise therapy is feasible and safe with promising activity in localized prostate cancer.
Trial Registration
ClinicalTrials.gov Identifier: NCT03813615
This nonrandomized clinical trial examines 6 escalated exercise therapy dose levels ranging from 90 to 450 minutes per week for men with treatment-naive localized prostate cancer.
Introduction
Emerging evidence provides support for exercise therapy as a candidate anticancer strategy in solid tumors.1 In nonmetastatic prostate cancer, epidemiological studies have shown that higher postdiagnosis exercise is associated with substantial reductions in cancer progression and death.2,3,4,5 Preclinical studies have demonstrated promising results with exercise-conditioned plasma suppressing in vitro growth of human prostate cancer cell lines6 and substantial tumor inhibition from exercise treatment in xenograft models.7,8 Randomized clinical trials of exercise therapy investigating the effects of a single dose level (eg, 2 to 3 sessions of 30 to 45 minutes per week of aerobic or resistance training for approximately 12 weeks) on symptom control outcomes have demonstrated favorable safety and compliance in localized6,9,10 and advanced11,12,13 prostate cancer.
This evidence supports the development of exercise therapy as a candidate antitumor strategy in localized prostate cancer. According to the translational framework designed to facilitate development of exercise therapy as an anticancer strategy,14,15 the next step is conducting early-phase trials to guide the design of larger trials and selection of the recommended phase 2 dose (RP2D). Theoretically, exercise doses that are inversely associated with prostate cancer mortality could guide selection of the RP2D. However, this is imprudent, because exercise quantification in observational studies is imprecise. The exercise dose that is inversely associated with prostate cancer mortality has varied considerably across individual studies.2,3,4,5 Selecting the RP2D based on exercise therapy doses with symptom control benefits in prostate cancer is similarly flawed because to our knowledge, all trials to date have only investigated 1 dose of exercise therapy, and dose(s) conferring symptom control vs antitumor benefit are likely distinct.16 In drug development, the RP2D is empirically determined from dose-finding phase 1 trials.17 To our knowledge, comparable trials of exercise therapy have not been conducted in any setting.
PRESTO-1 was a phase 1a dose-finding trial of neoadjuvant exercise therapy in patients with localized prostate cancer. In this article, we report the feasibility, safety, lifestyle and physiological response, and tumor biological activity of exercise therapy. The primary objective was to identify the RP2D.
Methods
Patients and Study Design
Using a single-center, phase 1a nonrandomized clinical trial, patients with histologically confirmed treatment-naive localized prostate cancer who were scheduled for surgical resection with at least a 2-week window before surgery at Memorial Sloan Kettering Cancer Center (MSK) were enrolled (Supplement 1). Other major eligibility criteria were reporting less than 30 minutes per week of moderate or vigorous exercise18 and no contraindications to moderate exercise.19 Eligible patients were allocated to 1 of 6 escalated exercise therapy dose levels: (1) 90 minutes per week with approximately 30 minutes per treatment, 3 times weekly; (2) 150 minutes per week with 30 minutes per treatment, 5 times weekly; (3) 225 minutes per week with approximately 45 minutes per treatment, 5 times weekly; (4) 300 minutes per week with approximately 60 minutes per treatment, 5 times weekly; (5) 375 minutes per week with approximately 60 to 75 minutes per treatment, 6 times weekly; and (6) 450 minutes per week, with approximately 60 to 90 minutes per treatment, 7 times weekly. Intrapatient dose escalation was not permitted. All study procedures were reviewed and approved by the MSK institutional review board. All patients provided written informed consent before the initiation of any study procedures. Race and ethnicity were self-reported and extracted from the medical record. This study followed the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) reporting guideline. Full methods are provided in the eMethods in Supplement 2.
Digitized, Decentralized Trial Platform
To conduct this trial, we created the digital platform for exercise, a fully digitized, decentralized, patientcentric approach. The digital platform was designed to enhance all aspects of exercise therapy clinical trials: patient identification, enrollment, and retention; exercise therapy administration; and longitudinal, near-continuous monitoring of lifestyle and physiological changes during exercise therapy. The digital platform involved remote electronic consent using video conferencing followed by shipment of an electronic tablet, treadmill, and several Bluetooth-enabled health devices (ie, smartwatch, a blood pressure monitor, body composition scale, and glucose monitor) to patients. This enabled all study procedures to be conducted remotely in patients’ homes. It also permitted enrollment of patients within a 100-mile radius of MSK’s main campus.
Study Treatment
Exercise therapy was administered across 3 to 7 individual treadmill walking sessions per week for 2 to 12 consecutive weeks, depending on the dose level allocation and preoperative window. After a 1-week ramp-up, all subsequent sessions were conducted at approximately 60% to 85% of patients’ individually determined pretreatment submaximal exercise capacity for approximately 30 to 90 minutes per session. Intensity was prescribed based on workload (the speed and incline) and heart rate response as measured during the pretreatment submaximal exercise capacity test. All sessions were performed remotely with real-time video monitoring by study exercise physiologists and continuous heart rate monitoring. Adverse events (AEs) requiring planned prescription dose reduction were performed according to standardized criteria (eMethods in Supplement 2).
Dose Allocation, Feasibility, and Safety
Patients were allocated to dose levels, with a modified continuous reassessment method (mCRM) assuming the dose-feasibility association followed a hyberbolic tangent model and using real-time feasibility (compliance) data to determine dose allocation.20,21 Feasibility was evaluated by relative exercise dose intensity (REDI), which was the ratio of the completed to planned dose for each exercise therapy session per patient. The mean REDI per patient was then calculated over the study period.22 Toxic effects grading was performed according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0. Safety data were monitored continually by the investigators and data evaluation committee.
Tumor Biological Activity
Two tumor biological activity end points were evaluated: (1) tumor cell proliferation (Ki67) measured in formalin-fixed paraffin-embedded tumor samples obtained at diagnosis (pretreatment) and radical prostatectomy (postintervention) and (2) prostate-specific antigen (PSA) in fasting plasma measured at pretreatment and approximately 2 days before surgical resection (postintervention). Tumor cell Ki6723,24,25 and PSA levels26,27 are associated with biochemical and clinical recurrence in localized prostate cancer. Ki67 has been validated as a tumor biomarker of responsiveness to neoadjuvant lifestyle interventions in men with localized prostate cancer.28 Tumor cell proliferation was measured by the percentage of Ki67-positive cells (ie, Mib-1 monoclonal antibody, 1:200 dilution; Dako29,30), while PSA levels were determined on the Beckman DXi 600 analyzer using the Access Hybritech 2-site immunoenzymatic assay in fasted plasma samples collected either via remote (in-home) blood collection or a standard-of-care visit to MSK.
Changes in Patient Lifestyle and Physiology
To examine alterations in lifestyle states that could confound treatment effects, we assessed (1) near-continuous diurnal and nocturnal patterns (ie, sleep, mobility patterns) using a smartwatch (Withings Steel HR) and (2) dietary intake at pretreatment and postintervention using a dietary mobile application (Bitesnap). To assess physiological changes during treatment we evaluated (1) exercise capacity as assessed by a submaximal treadmill exercise tolerance test conducted remotely in patients’ homes with real-time monitoring at pretreatment and postintervention, (2) body weight and body composition as assessed daily using a wireless scale (Withings Body+), (3) resting heart rate as evaluated every 10 minutes through the entire day using the smartwatch, (4) resting blood pressure as assessed daily using a wireless blood pressure monitor (Withings BPM Connect), and (5) interstitial fluid glucose levels using continuous glucose monitoring (CGM; Abbott Freestyle Libre Pro system) as assessed every 15 minutes through the entire day for the whole study period.
Statistical Analysis
As prespecified, an exercise therapy dose level was considered feasible if 70% or more of patients achieved an REDI of 75% or greater (over the entire planned treatment period). An REDI of less than 75% was considered nonfeasible. Feasibility was summarized using descriptive statistics. No prespecified thresholds were selected to evaluate whether exercise therapy had biological activity. Data were summarized descriptively with means and 95% CIs, with a mean negative change in Ki67 or PSA level considered indicative of biological activity. The association between dose level and change in Ki67 and PSA levels was also depicted graphically using a spline. To provide context for the activity of exercise therapy, PSA level changes (from diagnostic biopsy to surgical resection) were evaluated in a cohort of 24 patients with localized prostate cancer who were treated with radical prostatectomy at MSK (external control) using archival blood samples between June 2020 and January 2023 and with a 3-week to 6-week preoperative window. Changes in patient lifestyle and physiological outcomes were assessed by comparing the mean (95% CI) for each variable during the first 7 days of the intervention and final 7 days of the intervention.
Results
Patients were assessed for eligibility between June 2019 and January 2023. A total of 53 patients were enrolled. The median age was 61 years (range, 47-74 years), 3 patients (6%) were Asian, 9 patients (17%) were Black or African American, 36 patients (68%) were White, and 35 (66%) presented with at least 1 significant concomitant comorbidity (Table). Fifty-one patients (96%) completed postintervention procedures and underwent surgical resection. Two patients (3.7%) were lost to follow-up due to opting not to proceed with surgery (n = 1 for 225 minutes per week; n = 1 for 450 minutes per week). The study flow chart is presented in Figure 1. Patients resided within a mean (range) of 39 (6-90) miles from the MSK main campus. The mean (range) length of exercise therapy was 4.1 (2.0-12.0) weeks, with a mean (range) of 18 (3-48) completed sessions per patient (Figure 2).
Table. Patient Demographic and Pretreatment Characteristics.
| Characteristic | All patients (N = 53), No. (%) |
|---|---|
| Age, median IQR, y | 61 (56-66) |
| Weight, median (IQR), kg | 93 (88-103) |
| BMI, median (IQR) | 29 (26-33) |
| Prostate-specific antigen level, median (IQR), ng/mL | 5.7 (3.9-7.8) |
| Race | |
| Asian | 3 (6) |
| Black or African American | 9 (17) |
| White | 36 (68) |
| Missing | 5 (9) |
| Current smoker | 1 (2) |
| Comorbid conditions | |
| Hypertension | 25 (47) |
| Hyperlipidemia | 32 (60) |
| Diabetes | 7 (13) |
| Coronary artery disease | 4 (7) |
| Pulmonary disease | 1 (2) |
| None of these comorbidities | 18 (34) |
| Exercise history, median (IQR), min/wka | 0 (0-0) |
Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared).
SI conversion factor: for prostate-specific antigen, to convert to μg/L, multiply by 1.
Exercise was defined as structured, recreational physical activity of moderate or vigorous intensity during the month before study enrollment.
Figure 1. Study Flowchart.
PSA indicates prostate-specific antigen.
Figure 2. Exercise Therapy Treatment Summary.
Total number of exercise sessions completed by each patient in each dose level.
Feasibility and Safety
The first patient enrolled using the mCRM dose-escalation design was allocated to the lowest dose level (90 minutes per week). Compliance was 75% or greater. According to the mCRM adaptive method, subsequent enrolled patients were allocated to the highest dose level (375 minutes per week). Ten patients were treated at a 375 minutes per week dose with compliance of 75% or greater for all patients. As such, a sixth dose level of 450 minutes per week was added. The next 5 enrolled patients were treated at 450 minutes per week; compliance was 75% or greater for all patients. To examine the feasibility and activity of lower exercise therapy doses, we next allocated patients to the 90, 225, and 300 minutes per week dose levels in chronological order. The final dose allocations were 90 minutes per week (n = 4), 150 minutes per week (n = 9), 225 minutes per week (n = 9), 300 minutes per week (n = 10), 375 minutes per week (n = 11), and 450 minutes per week (n = 10).
Nine of 53 patients (17%) did not achieve the prespecified acceptable compliance (<75% REDI): No patients doing 90 minutes per week, 2 of 9 (22%) patients doing 150 minutes per week, 1 of 9 patients (11%) doing 225 minutes per week, 3 of 10 (30%) doing 300 minutes per week, 1 of 11 (9%) doing 375 minutes per week, and 2 of 10 (20%) doing 450 minutes per week. Thus, as per the protocol-specified definition, all dose levels were feasible. No grade 3 events were observed in any patient at any dose level. Twenty of 53 patients (38%) experienced at least 1 nonserious AE, most frequently tachycardia and exercise-induced hypertension (eTable 3 in Supplement 2).
Changes in Lifestyle and Patient Physiology
Mean changes and 95% CIs in patient lifestyle and physiology assessments for all dose levels combined and per dose level are presented in eTable 4 in Supplement 2. For all dose levels combined, exercise capacity increased, whereas body weight and resting systolic and diastolic blood pressure decreased. The proportion of sedentary and active time also decreased. No changes in dietary intake were observed. Changes in patient lifestyle and physiology outcomes varied by exercise therapy dose level.
Tumor Biological Activity
Adequate paired formalin-fixed paraffin-embedded tumor samples were available for 47 patients (89%) and included in the Ki67 analysis. The mean (95% CI) change in Ki67 from pretreatment to postintervention in each dose level was 5.0% (95% CI, –4.3% to 14.0%) for 90 minutes per week, 2.4% (95% CI, –1.3% to 6.2%) for 150 minutes per week, –1.3% (95% CI, −5.8% to 3.3%) for 225 minutes per week, –0.2% (95% CI, –4.0% to 3.7%) for 300 minutes per week, –2.6% (95% CI, –9.2% to 4.1%) for 375 minutes per week, and 2.2% (95% CI, –0.8% to 5.1%) for 450 minutes per week (Figure 3A). Paired plasma PSA levels were available for 42 patients (79%) and included in the PSA analysis. The mean (95% CI) change in PSA levels from pretreatment to postintervention in each dose level was 1.0 ng/mL (95% CI, –1.8 to 3.8 ng/mL; to convert to μg/L, multiply by 1) for 90 minutes per week, 0.2 ng/mL (95% CI, –1.1 to 1.5 ng/mL) for 150 minutes per week, –0.5 ng/mL (95% CI, –1.2 to 0.3 ng/mL) for 225 minutes per week, –0.2 ng/mL (95% CI, –1.7 to 1.3 ng/mL) for 300 minutes per week, –0.67 ng/mL (95% CI, –1.7 to 0.4 ng/mL) for 375 minutes per week, and –0.9 ng/mL (95% CI, –2.4 to 0.7 ng/mL) for 450 minutes per week (Figure 3B). In the external control group, the mean (SD) change in PSA levels from time of diagnostic biopsy to surgical resection was 2.08 ng/mL (2.00 ng/mL). The patient characteristics of the external control group were similar to the exercise therapy intervention patients (eTable 5 in Supplement 2). Finally, the dose level–activity response spline analysis revealed a nonlinear association. Compared with doses less than 225 minutes per week, 225 minutes per week and greater was associated with decreases in Ki67 (only to 375 minutes per week) and PSA levels; higher doses beyond 225 minutes per week provided marginal additional benefit (eTable 5 in Supplement 2).
Figure 3. Tumor Biological Activity.
A, Absolute percentage delta changes in tumor cell proliferation (Ki-67) from pretreatment to postintervention per exercise therapy dose level. B, Absolute delta changes in prostate-specific antigen (PSA; ng/mL [to convert to μg/L, multiply by 1]) from pretreatment to postintervention per exercise therapy dose level.
Determination of the RP2D
As per protocol, since all dose levels were feasible, the dose with the largest reductions in Ki67 and PSA levels would be selected as the RP2D. Reductions in Ki67 and PSA levels were observed in dose levels of 225 to 375 minutes per week. Reductions in PSA levels with exercise therapy were also observed in the context of increases in PSA levels (2.08 ng/mL) among the external control cohort. The 375 minutes per week dose level was associated with the largest numerical estimate reductions in Ki67 and PSA levels; however, these differences were marginal compared with 225 minutes per week. This numerical benefit must be weighed against the substantive additional weekly time commitment required compared with 225 minutes per week. Overall, considering the feasibility–tumor activity ratio, 225 minutes per week (approximately 45 minutes per treatment, 5 times weekly) was selected as the RP2D.
Discussion
This phase 1a nonrandomized clinical trial demonstrated the feasibility and safety of neoadjuvant exercise therapy in inactive patients with localized prostate cancer. To our knowledge, this study is the first phase 1a trial of exercise therapy in the oncology or nononcology setting.14 Conduct of this trial was facilitated by 2 methodological approaches developed to facilitate clinical investigation of exercise therapy. First, since traditional phase 1 parameters (eg, pharmacokinetics, maximum tolerated dose) generally do not apply to exercise therapy,14 we adapted metrics from oncology drug trials to establish a new method of quantifying feasibility (REDI)31 that permitted identification of the maximal feasible dose. Second, we leveraged digital technology, permitting all study procedures to be conducted remotely in patients’ homes. This was associated with considerably reduced patient burden, permitting investigation of much higher exercise therapy doses than traditionally tested.32 It also allowed testing of dose levels at high fidelity while improving the speed and diversity of recruitment.
Consistent with phase 1 studies of contemporary oncology therapeutics,33 we selected the RP2D based on feasibility together with consideration of tumor biological activity. Evaluation of tumor activity in patients with advanced disease (the traditional setting for phase 1 oncology trials) is likely not appropriate for phase 1 studies of exercise therapy, especially as single agent.14 The neoadjuvant context permits testing of candidate strategies on validated surrogates.34,35 Using standard biomarkers of antitumor activity exercise therapy showed promising tumor biological activity, but in a nonlinear (curvilinear) fashion: lower doses were subtherapeutic, whereas a therapeutic range of 225 to 375 minutes per week conferred biological activity; activity of higher doses (450 minutes per week) was subtherapeutic, at least as evaluated by Ki-67. The observed nonlinear (curvilinear) response to increasing doses of a substance or therapy was reminiscent of hormesis.25 Exercise doses less than and greater than a homeostatic zone (therapeutic range) may confer suboptimal tumor activity. Observational studies investigating the association between postdiagnosis exercise and cancer outcomes have reported similar findings.36,37 Further research investigating this phenomenon in prostate cancer and other solid tumors is required given the potential clinical implications.18,38,39 Although biologic activity of 375 minutes per week was numerically superior to 225 minutes per week, the additional benefit must be weighed against the substantive additional 150 minutes per week time commitment. Thus, 225 minutes per week (approximately 45 minutes per treatment, 5 days weekly) was selected as the RP2D. That is, the lowest feasible dose with activity. Identification that exercise therapy doses of 225 to 375 minutes per week conferred biological activity is contrary to current guidelines from the American College of Sports Medicine that recommend exercise therapy between 90 to 150 minutes per week for patients with cancer.38,39 A phase 2 randomized clinical trial has been initiated (NCT05751434) to investigate the efficacy of longer-term exercise therapy at the RP2D on prostate cancer correlative end points and clinical progression. Whether higher doses beyond the standard recommendation of 150 minutes per week are required to confer biological activity in other solid tumors is not known. This question will be evaluated in PRESTO-2, a planned phase 1b dose-expansion trial evaluating the feasibility and activity of neoadjuvant exercise therapy at the RP2D across multiple solid tumors.
Limitations
This study had limitations. First, the results were limited to inactive men with localized prostate cancer and do not generalize to those with higher activity levels or other solid tumors for whom exercise therapy feasibility (compliance) and biological activity may be distinct. Relatedly, we likely recruited a cohort of men who were highly motivated to voluntarily participate in a lifestyle intervention, potentially affecting the generalizability of our findings to all men with a diagnosis of prostate cancer. Second, our trial consisted of highly structured exercise therapy of 1 exercise modality with individualized supervision; feasibility, safety, and activity could differ within other conditions and with different exercise modalities (eg, resistance training). A final limitation is the very short length of the treatment intervention; the feasibility and activity of exercise therapy requires testing over the long term among larger cohorts.
Conclusions
In this nonrandomized clinical trial, neoadjuvant exercise therapy was well tolerated, with doses 225 to 375 minutes per week showing promising activity in treatment-naive localized prostate cancer. A total of 225 minutes per week was selected as the RP2D. These data and methods may facilitate further development of exercise therapy as a candidate anticancer strategy in prostate and other solid tumors.
Trial protocol
eMethods.
eTable 1. Exercise therapy dose modification guidelines
eTable 2. Reasons for missed exercise therapy sessions
eTable 3. Adverse events during exercise therapy sessions
eTable 4. Changes in patient physiology, lifestyle states, and dietary intake
eTable 5. Comparison of medical and demographic characteristics of exercise therapy patients and external control patients
eReferences
Data sharing statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
eMethods.
eTable 1. Exercise therapy dose modification guidelines
eTable 2. Reasons for missed exercise therapy sessions
eTable 3. Adverse events during exercise therapy sessions
eTable 4. Changes in patient physiology, lifestyle states, and dietary intake
eTable 5. Comparison of medical and demographic characteristics of exercise therapy patients and external control patients
eReferences
Data sharing statement