Evaluating relugolix for the treatment of prostate cancer in real-world settings of care: the OPTYX study protocol

Prostate cancer is the most prevalent cancer in men and the second leading cause of cancer death in men in the USA. In 2023, American Cancer Society estimated 288,300 new prostate cancer cases (29% of male cancer cases), with 34,700 estimated deaths (11% of male cancer death) [1]. Prostate cancer incidence increases with increasing age, with the average age at the diagnosis time being 66 years. Advanced prostate cancer can encompass a variety of stages, ranging from locally advanced disease to widely disseminated metastatic disease.

Androgen deprivation therapy (ADT) has been the foundation of systemic treatment for men with advanced prostate cancer for more than 70 years [2]. ADT is recommended as the primary systemic therapy for regional or advanced diseases. It is used in combination with radiation in localized or locally advanced prostate cancers, or in conjunction with abiraterone with/without radiation for high-risk localized or regional prostate cancer or with enzalutamide for biochemical recurrence [3–5]. ADT with treatment intensification, including docetaxel, abiraterone acetate and antiandrogens are recommended for patients with metastatic castration-sensitive prostate cancer (mCSPC). ADT is continued with or without certain secondary hormone therapies depending on prostate specific antigen (PSA) doubling time in patients with castration-resistant prostate cancer (CRPC) and with secondary hormone therapies, chemotherapies, immunotherapies, radiopharmaceuticals and/or targeted therapies in mCRPC patients [3–5].

Gonadotropin-releasing hormone (GnRH) receptor agonists and antagonists have been utilized as ADT [6], but they suppress testosterone through different mechanisms of action [7]. GnRH agonists bind to the GnRH receptor in the pituitary gland inducing luteinizing hormone release (LH) and follicle-stimulating hormone (FSH), causing an initial increase in testosterone prior to suppression within a few weeks. Conversely, treatment with antagonists results in a direct decrease of FSH and LH secretion, causing a direct decrease of the testicle's testosterone production. Most men in developed countries receive medical ADT instead of surgical orchiectomy that results in permanent androgen deprivation [8]. Long-term downregulation and desensitization of the hypothalamic–pituitary–gonadal axis may be achieved using long-acting depot injectable GnRH receptor agonists (including leuprolide and goserelin) [9]. However, the initial clinical testosterone flare caused by these GnRH receptor agonists may include symptoms such as bone pain, obstructive urinary symptoms or rarely, ureteral obstruction or spinal cord compression [9,10]. Thus, initial combination with antiandrogens is required to avoid the associated testosterone flare and the delay of up to 4 weeks in achieving castration. Additionally, testosterone recovery after stopping GnRH agonist therapy may take months or years depending on several factors, including age and therapy length.

Relugolix [11], a first-in-class, oral GnRH antagonist, was developed to address some limitations of the available ADT therapies. In multiple phase I and phase II studies, relugolix lowered testosterone to levels <50 ng/dl for the treatment of men with advanced prostate cancer by directly inhibiting pituitary release of LH and FSH [12–15]. The pivotal study HERO, a phase III, international, randomized, open-label, parallel group study, evaluated the efficacy and safety of oral daily relugolix 120 mg (after a loading dose of 360 mg) compared with leuprolide depot injection in patients with hormone sensitive advanced prostate cancer who required at least 1 year of continuous ADT [16]. Results from the HERO study demonstrated testosterone suppression to castrate levels in 96.7% of patients from day 29 through 48 weeks, which was superior (p < 0.001) to leuprolide (88.8%) [16]. In the prespecified safety analysis of major adverse cardiovascular events (MACE) events in all patients in the study, relugolix was associated with a 54% lower risk (hazard ratio, 0.46; 95% CI; 0.24 to 0.88) of MACE, relative to leuprolide. The most common adverse events (AEs) observed in relugolix-treated patients were hot flash, fatigue, constipation, diarrhea and arthralgia [16]. Patients were followed for safety and efficacy for 48 weeks in the phase III study. Among a subgroup of 184 patients who were monitored for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng/dl in the relugolix group and 58.6 ng/dl in the leuprolide group [16]. Limited combination were studied, however doublet therapy with Androgen Receptor Pathway inhibitor (ARPi) is increasingly becoming a standard of care in multiple disease states in prostate cancer. To supplement clinical trial data, it is therefore important to generate additional evidence about the safety and effectiveness of relugolix in patients with prostate cancer in routine clinical care and how quality of life changes during and following relugolix cessation.

A patient registry can be a powerful research methodology to collect and observe disease natural history and real-world outcomes in prostate cancer that can supplement clinical trial data [17]. Observational studies of patients may provide important safety signals and effectiveness information about the use of concomitant medications and adjunctive therapies in clinical practices. Many healthcare decision makers may benefit from the value of longitudinal information provided by a patient registry. As of May 2023, there were 36 listed prostate cancer registries on ClinicalTrials.gov recruiting patients, including key studies including the PROMISE and IRONMAN studies [18,19].

Rationale

Since GnRH receptor agonists (e.g., long-acting leuprolide acetate depot injections) [20] have been the standard of care and most used modality of ADT for the past 20 years, most data and evidence used to guide clinical use and guidelines for ADT have been built upon information from leuprolide utilization. The OPTYX registry study focuses on patients initiating or who have initiated treatment with relugolix within 1 month before study enrollment, remaining on treatment after enrollment. The prospective design captures key patient characteristics and allows longitudinal follow-up for effectiveness, treatment patterns, adherence, persistence, patient-reported outcomes (PROs) and safety in clinical settings. ADT usage patterns such as prescriber specialty (e.g., urologist, medical oncologist or radiation oncologist), reasons for ADT administration (e.g., adjuvant/neoadjuvant, metastases), therapy length, and if ADT is continuous or intermittent will be explored. Real-world data usage will not only enrich the evaluation of patient experiences and outcomes in clinical settings but also complement traditional clinical trial data, addressing limitations associated with selected population and study designs. Since the HERO study did not include an extension phase, observing patients post-therapy cessation will provide insights into the prostate cancer trajectory, health outcomes and health-related quality of life (HRQOL) in these patients.

A diversity, equity and inclusion plan has been developed to actively address disparities and ensure the inclusion of high-risk and typically underrepresented populations in this study. The plan includes utilizing available data (e.g., National Institute of Health, Center of Disease Control and Census Data) to identify locations with the highest prostate cancer case counts in Black men and other populations of interest including Hispanic men, men from rural areas, and identifying potential investigators in those areas. Also, informed consent and patient questionnaire forms are available in both English and Spanish.

Objectives

Study objectives

The goal of this study is to generate additional evidence about the clinical effectiveness, including PSA and testosterone kinetics and disease progression), and HRQOL of patients with prostate cancer treated with relugolix in routine clinical care and the clinical course during treatment with and following cessation of relugolix.

Primary study objectives

To describe patient demographics and clinical characteristics of patients with prostate cancer who are initiating treatment with relugolix in real-world practice settings.

To understand the safety and health outcomes of patients with prostate cancer treated with relugolix along with changes in their HRQOL.

Secondary objectives

To understand the prostate cancer progression during treatment with and following cessation of relugolix therapy including clinical or disease progression, co-morbidities and death.

To describe patient adherence and persistence, including reasons for changes with relugolix treatment.

Patients & methods

Setting

This study will be conducted at participating centers/clinics in university-affiliated hospitals, community hospitals, Veterans Affairs and other integrated healthcare systems and independent practices.

Study population

The study will target enrollment of approximately 1000 patients. A study goal is to enroll at least 20% of patients with metastatic prostate cancer and 10% of patients with castrate resistant prostate cancer to provide a representative assessment and additional data on these patient populations. The decision to initiate treatment with relugolix should be made prior to study enrollment. The study population includes a broad range of patients (e.g., patients with local, locally advanced, metastatic, PSA or clinically recurrent after primary treatment for prostate cancer), treatment circumstances (e.g., monotherapy, combination therapy or intermittent therapy with relugolix), and settings (e.g., urology, oncology, radiation oncology) representative of the real-world patterns of care.

All eligible patients will be invited to enroll into the study to obtain data from diverse populations. Underrepresented and diverse patient populations are an important focus for OPTYX study. To support their participation in this study, the study team is actively seeking to broaden site selection (e.g., using communication channels, ensuring sites are aware of available resources, etc.) and study interest by using site feasibility questionnaires with study sites. These tools have been used to assess their treatment population, allowing the focus on sites with a diverse patient population, including areas with specific racial and ethnic groups (i.e., Black, Hispanic/Latino, Asian). The recruitment goal is for at least 15% of the study participants to represent Black patients. Additionally, the inclusion of veterans, who represent a high-risk population of prostate cancer patients, is being pursued. Finally, the informed consent form and patient reported outcomes instruments have been translated into Spanish for ease of use with Spanish speaking participants. In general, collaboration with patient advocacy groups has been planned to increase awareness and education related to advanced prostate cancer and this study design.

Inclusion criteria

Eligibility criteria include patients aged 18 or older diagnosed with prostate cancer and initiating treatment with relugolix at the time of enrollment or within the 1 month prior to enrollment and who remain on treatment at enrollment; patients who have reviewed and signed the informed consent form (ICF); and patients who are willing and able to complete PRO assessments during the study.

Exclusion criteria

Patients are excluded if they have a history of surgical castration; have a medical or psychiatric condition that precludes participation in the opinion of the treating physician; and/or have an original treatment plan that is intended to be less than a total of 4 months of relugolix.

Study design

This is a multi-center, prospective, observational study. All patients with prostate cancer who are initiating treatment or have initiated treatment with relugolix in the 1 month prior to enrollment in the study and who remain on treatment at the time of enrollment are invited to participate in the study. Patients who used other medical androgen deprivation therapy prior to starting relugolix are also eligible. This study is designed to characterize the effectiveness, adherence, persistence, HRQOL and safety profile of relugolix.

Patients will undergo clinical assessments and receive standard medical care as determined by the patient's treating physician in a real-world practice setting. Patients will not receive experimental intervention or treatment as part of their participation in this study. No mandatory visits, tests or clinical assessments are required for this study.

Patients will be followed prospectively for up to 5 years from the date of signed informed consent (enrollment) in order to ascertain patient outcomes for this time period (Figure 1). If treatment with relugolix has been discontinued, patients may be followed for up to 2 years after discontinuation. Follow-up will end with withdrawal of consent, loss to follow-up, death or end of study data collection, whichever comes first.

For patients who initiate relugolix therapy in the 1 month prior to study enrollment, retrospective data will also be collected from the time of treatment initiation.

Assessment & collection of clinical data of interest

Data will be extracted from the patient's medical records by site personnel. Once written informed consent has been obtained, study site personnel will complete the data collection at enrollment and throughout the study period for each patient (Table 1). Follow-up data for patient visits will be recorded in the patient chart in accordance with the clinical site's standard of care or clinical judgment. No specific mandated clinical assessments are to be performed as part of study participation. All visits will be scheduled and conducted according to the clinical site's routine clinical practice. Sites will be encouraged to extract data at least every 6 months.

Data will be entered into electronic Case Report Forms (eCRFs) designed for this study at the time of collection or, at a minimum, every six months by the site. Table 2 indicates the assessments that will be captured through the course of the study, noting that there may be missing data if any assessments are not performed as part of routine clinical practice. Data will be extracted from the medical records and entered into the electronic data capture (EDC) following clinic visits. Secondary data including insurance and pharmacy claims data and medical records, to capture data on healthcare encounters that occur outside of the setting of the treating physician, may be obtained electronically and imported into the study database on a periodic basis at a frequency to be determined.

Patient-reported outcomes

Although no mandatory visits, tests, or clinical assessments are required, patient assessments, including HRQOL and treatment adherence, are important components in this study. PROs will be collected at the following timepoints: baseline (FACT-P only), 3 and 6 months after baseline, then at every 6 months during the follow-up period, and at study and/or treatment discontinuation. If relugolix treatment has been discontinued, patients will also be encouraged to complete QOL PROs at the time of discontinuation, and then at 3 and 6 months, and 1 year after stopping relugolix (Table 3).

Follow-up & loss to follow-up

The study operations team plan to conduct regular contact calls with the sites to ensure that data are being regularly entered, and particularly when no data are entered by the site for an enrolled patient within 7 months of the last data entry time point, to confirm the patient's status and whether the patient is still under the healthcare provider's (HCP) care. Lost to follow-up is defined when no new data have been received or logged into source documents by the participating site for over 12 months and attempts to contact the patient and/or secondary contacts by phone calls and letter have been unsuccessful and exhausted. In this case, the last data collection date will be considered the end of their study participation.

Adverse event reporting

Selective safety data, including all SAEs and any nonserious AEs that lead to the discontinuation of relugolix will be entered into the eCRF upon notification by the patient (e.g., reported via phone call) or upon identification from electronic medical record review. All SAEs and updated SAE data, independent of causality and along with an assessment of severity and causality, will be reported to the sponsor within 1 business day of the treating physician/site being made aware using a Safety Report Form (SRF). The treating physician should promptly notify the sponsor of any SAEs that are considered to be reasonably related to relugolix, including death, at any time after a patient has been discharged from the study. All SAEs should be followed until resolution, stabilization, the event is otherwise explained, or the patient is lost to follow-up. The treating physician is obligated to assess the relationship between relugolix treatment and the occurrence of each SAE or nonserious AEs that leads to the discontinuation of relugolix based on clinical judgement. A reasonable possibility of a relationship conveys that there are facts, evidence, and/or arguments to suggest a causal relationship, rather than a relationship that cannot be ruled out. Alternative causes, including underlying disease(s), concomitant therapy, other risk factors and the temporal relationship of the event to study treatment administration will be considered and investigated.

Statistical approach

No formal hypotheses will be tested in this study. At interim enrollment milestones (e.g., n = 250, 500, etc.), demographic, medical history and treatment patterns, may be summarized using descriptive statistics (i.e., number and percent for categorical variables, mean, standard deviation, standard error, median, minimum and maximum for continuous variables).

When statistical testing is appropriate, continuous variables will be compared using Student's T, Wilcoxon, analysis of variance (ANOVA) or Kruskal-Wallis tests, for the variable distribution and groups under consideration. Categorical variables will be compared using chi-square or Fisher's exact tests. For time-to-event analyses, Kaplan–Meier method will be used for generating estimates. The median survival time and 95% CI will be provided (if applicable). Log rank test or Cox regression model may be used to evaluate differences between subgroups, adjusting with or without covariates.

The FACT-P questionnaire [21], the primary HRQOL measure in this study, comprises 39 items (27 assessing physical, social/family, emotional and functional well-being, and 12 composing the Prostate Cancer Subscale). The questionnaire is scored by summing the responses to individual items (5-point Likert-type scale) to obtain subscale and total scores. Change in FACT-P will be analyzed using mixed effects model with repeated measures (MMRM).

The frequency and percentage of patients experiencing any SAEs or nonserious AEs leading to relugolix discontinuation will be summarized by system organ class and preferred Medical Dictionary for Regulatory Activities (MedDRA) terminology. SAEs of hospitalizations and deaths will be summarized descriptively. The frequency of SAEs and any nonserious AEs leading to relugolix discontinuation will be analyzed by treatment year (1st, 2nd, etc. year post-treatment initiation) and overall. Incidence rates (per 100 person years) will also be calculated for each time period and overall.

All reasonable attempts to obtain information related to outcomes will be made. Missing data will be addressed using methods appropriate to the missing pattern (i.e., missing completely at random, missing at random and informative missingness). Two-sided alpha of 0.05 will be considered as significant. Data for all patients available will be evaluated for all end points at each timepoint, subgroup analyses (as appropriate), details on important potential and known confounders, and further analysis details will be described in the statistical analysis plan.

Protection of human subject

Prior to the collection of any study related data, IRB approval of the protocol, informed consent and all patient enrollment materials will be obtained per site. The study will be conducted in accordance with the ethical principles originating from the Declaration of Helsinki, applicable privacy laws and local regulations per participating site. This study will be conducted in accordance with the Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the International Society for Pharmacoepidemiology (ISPE, 2008), the Guide on Methodological Standards in Pharmacoepidemiology issued by The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), the Guideline on Good Pharmacovigilance Practices (GVP) Module VIII Post Authorization Safety Studies and the Declaration of Taipei.

Data dissemination

Study sponsors will seek to prepare one or more abstracts or manuscripts for publication including a description of the study methods and the results of this observational study to be submitted to medical congresses and/or peer-reviewed journals. Authors, Steering Committee members and study sponsors will adhere to the prevailing standards for ‘Good Publication Practice' following current guidelines and recommendations (e.g., GPP3 Guidelines) [22] and the criteria for authorship established by the International Committee of Medical Journal Editors (ICMJE) [23].

Discussion & future perspectives

Relugolix (ORGOVYX), the first US FDA approved oral GnRH receptor antagonist, provides a novel treatment option for ADT in advanced prostate cancer. Real-world evidence on relugolix is maturing. McKay et al. studied patients treated with ADT: 88.1% with leuprolide and 6.0% with at least one prescription for relugolix [24]. The results show that, in the first year relugolix was available, the proportion of patients using relugolix combination with other commonly used prostate cancer therapies was higher than in leuprolide treated patients (22.5 vs 19.5%). Combination use in prostate cancer patients new to ADT was higher for relugolix users (15.8%) than for leuprolide users (10.9%). In both groups, second-generation anti-androgens were the most frequent type of combination therapy used. Kasparian et al., analyzed real-world data from a high-volume treatment center [25]. In a sample of 101 patients who were prescribed relugolix, 71 of the 91 patients consenting to the study had at least one prescription filled with a median follow-up of 5 months. The authors found 93% of patients filling their medication never reported missing a relugolix daily dose, suggesting good therapy compliance. Clinically, 97% of relugolix patients showed improved or stable PSA levels and 100% had successful and stable castration rates where testosterone data was available (n = 61). The subset of patients who had switched from injectable leuprolide to relugolix reported tolerating relugolix similarly or better than their previous therapy. Finally, combination use with relugolix in this institution was identified in 34% of the patients, with the three most frequent treatments being enzalutamide, abiraterone acetate and bicalutamide. The authors observed and reported no new safety signals in patients taking relugolix in combination with AR-targeted agents or switching from injectable leuprolide, supporting the safety data reported in HERO study. In summary, both retrospective studies highlight the early real-world experience with relugolix.

The data from OPTYX study will further enable the evaluation of experience and outcomes to therapy that is not possible in a traditional clinical trial due to the limitations of a selected population and assessments. The prospective design enables the capture of important patient characteristics at baseline, and then provides longitudinal follow-up to capture information on effectiveness, treatment patterns, treatment adherence and persistence, PROs and safety outcomes. Real-world adherence, combination therapy with other prostate cancer medications (e.g., androgen receptor agents and chemotherapy), and the use of relugolix in patients with CRPC are areas where additional data are desired. Testosterone recovery after extended treatment with relugolix, and HRQOL outcomes will be important to practitioners. Data from OPTYX study will be used in publications which may include yearly updates on patient populations taking relugolix.

Given that this study will describe the clinical management of patients with advanced prostate cancer across a several treatment settings, there is a potential limitation due to variations in the standard of care with the potential for missing data for some measures. However, the heterogeneity of practice settings provides a broad picture of treatment patterns for these patients. Another limitation may be the approach that allows patients who began treatment 1 month prior to their study enrollment to be included to evaluate as large a population with diverse demographic characteristics as possible. This approach will not include patients who initiate relugolix and discontinue prior to enrollment, i.e., survivor bias. As ADT monotherapy is not a preferred option for most scenarios, consequently, the AE/PRO profiles and T recovery assessments may be skewed. Also, any SAEs that occur shortly after treatment initiation but prior to enrollment may not be noted by the physician and so may be underrepresented. A well-recognized limitation in a real-world practice setting is potential for confounding due to lack of comparability between the study cohort and the overall patient population with prostate cancer. Confounding may result from factors associated with outcomes of interest that are also associated with exposures of interest. Incidence rates (rather than incidence rate proportions) will be used to take advantage of all years of patient follow-up to improve precision of applicable effect estimates. Patient selection bias is a consideration, as motivation to consent to join the study can vary between patients for different reasons. Also, if prescribers and patients are not willing to participate, selection bias may occur, resulting in limited generalizability of the results. All eligible patients at each participating site can be invited to participate, minimizing the selection bias.

As of 10 May 2023, there were 84 patients enrolled in the study. The main type of providers prescribing relugolix to these patients were urologists (59 patients; 70.2%) followed by medical oncologists (14 patients; 16.7%), APP (Nurse Practitioners or Physician Associate/Assistants) (three patients; 3.6%), radiation oncologists (one patient; 1.2%), and others (six patients; 7.1%). An interim analysis of the first 100 patients is planned, which may result in a publication of the results.

Conclusion

This study will allow real-world understanding of the patient-reported and clinical outcomes of prostate cancer patients treated with relugolix in routine clinical care and their clinical trajectory following cessation of the therapy.