Injectable GnRH receptor agonists have been shown to improve cancer control when combined with radiotherapy (RT) (1). Androgen deprivation therapy (ADT) in conjunction with conventionally fractionated radiation therapy significantly improves metastases-free and overall survival in men with prostate cancer (2). As with external beam radiation therapy (EBRT), early data suggests that the addition of ADT to SBRT for unfavorable prostate cancer may also reduce local persistence of disease and biochemical recurrence (3, 4). Unfortunately, ADT combined with RT remains underutilized, possibly due to bothersome persistent side effects and its potentially negative impact on cardiovascular comorbidities (5).

Relugolix is an oral ADT that suppresses gonadotropic release from the pituitary gland, thus decreasing concentrations of testosterone (6). The HERO study investigated the efficacy of this oral GnRH receptor antagonist compared to GnRH agonist leuprolide. The randomized Phase 3 trial demonstrated the superiority of relugolix in achieving and maintaining castration (7). Men treated with relugolix maintained castration through 48 weeks at a rate of 96.7% compared to 88.8% with leuprolide (7). The study exhibited a 99% adherence rate with oral relugolix, although most patients had daily audible reminders to take their pill (7). Similarly, neoadjuvant/adjuvant relugolix (6 months) has been studied in unfavorable localized prostate cancer in combination with conventionally fractionated radiation therapy (79.2 Gy in 44 fractions) (8). With relugolix, 95% achieved castration (total testosterone < 50 ng/dL, 1.73 nmol/L) and 82% reached profound castration (total testosterone < 20 ng/dL; 0.7 nmol/L). As with the HERO study, interventions to improve adherence were utilized (8).

While oral ADTs have potential advantages, their real-world effectiveness is dependent on patient adherence (9). Non-adherence to ADT could lead to increased rates of biochemical recurrence and prostate cancer-specific death. Adherence is defined as taking a medication exactly as prescribed. Generally, an adherence rate of > 80% is required for optimal therapeutic efficacy. Unfortunately, medication non-adherence is common, with up to 50% of patients self-reporting non-adherence (10). The estimated rate of non-adherence in prostate cancer patients receiving oral anti-androgens for metastatic disease is 5-10% (11–14). Factors associated with non-adherence include advanced age, multiple daily doses, side-effect severity, length of use, and inadequate patient education (15). Bothersome side effects such as hot flashes, fatigue, and decreased libido may lead to drug holidays and/or early cessation (16). This may be a bigger problem in minority and other underserved populations (15, 16).

Currently, a test for relugolix serum levels is not clinically available. However, adherence can be measured using indirect methods (i.e., serum testosterone levels) or subjective measures, such as patient-reported outcomes (PROs). PROs allow for early assessment that is both affordable and non-invasive. The Simplified Medication Adherence Questionnaire (SMAQ) is a commonly used psychometrically validated questionnaire with six questions to quantify omissions and barriers to adherence (forgetfulness, carelessness, skipping doses due to adverse side effects) (17, 18). This information can be utilized to develop individualized approaches tailored to a patient’s specific reasons for and level of non-adherence.

Adherence to medications assessed by SMAQ has been studied for a variety of medications utilized in different disease states, such as chronic myeloid leukemia (CML), HIV, bipolar disorder, acute coronary syndrome (ACS), Parkinson’s disease, and more (18–25). These studies have identified numerous predictive factors of SMAQ-reported adherence, including patient education level, employment status, cognitive functioning, alcohol consumption, and negative attitude toward treatment (19–21). However, other studies utilizing the SMAQ have found no correlation between compliance and social demographic data (23, 25). Additionally, adherence to therapy has been shown to be affected by treatment-related toxicities and patient quality of life (22).

Limited data are available on patient adherence to oral ADT in men receiving radiation therapy for localized prostate cancer. Further knowledge in this area would aid in developing approaches to improve adherence. The objective of this study was to prospectively collect and report patient-reported relugolix adherence at the start of prostate SBRT for intermediate to high-risk prostate cancer. In addition, we demonstrate the feasibility of incorporating the SMAQ into daily clinical practice during a course of RT and its utility in improving drug adherence.

We conducted an IRB-approved, prospective study (IRB 12-1175) of men with prostate cancer treated with short-term relugolix and prostate SBRT at Georgetown University Hospital. Patient and treatment characteristics, such as age, race, partner status, comorbidities, BMI, and risk group, were acquired from the medical records.

This study utilizes a regimen combining an oral GnRH receptor antagonist, relugolix, and SBRT for localized prostate cancer. Hypofractionated and ultrahypofractionated radiotherapy (SBRT) has been shown to be an effective curative treatment option for patients with localized prostate cancer when compared to conventionally fractioned radiation therapy (CFRT), with favorable biochemical control and toxicity levels (28, 29). ADT can be utilized as a complementary treatment to SBRT, as studies have shown that a combination of the two modalities can provide improved outcomes (3, 4).

Drug adherence is an important consideration when utilizing oral androgen deprivation therapies in combination with prostate SBRT. Measuring serum testosterone levels is a commonly employed indirect measure to assess drug adherence (30). However, interval testosterone levels may not capture short-term drug interruptions that could negatively impact cancer control. A better understanding of patient adherence patterns would aid in designing approaches to improve it.

Prior studies of relugolix utilized daily reminders which likely improved compliance rates and ensured continued testosterone suppression (7, 8). Due to administrative burden, we did not utilize scheduled cues as part of our study. Nonetheless, our self-reported adherence (SMAQ) was medium (60-80%) and higher than previous studies utilizing the SMAQ questionnaire ( Table 4 ; 38-64%). Over 95% of patients reported taking the drug at the same time every day. It was reassuring that only 3% of patients skipped the medication due to bothersome side effects. The main reason for non-adherence was forgetfulness. However, the 20% of men who reported forgetting to take the medication is relatively low for an elderly male patient population (31). The results are reassuring, considering greater than a third of our patients were minorities, 22% were un-partnered and 12% had a moderate to severe comorbidity index ( Table 1 ).

Limitations of our investigation are secondary to its small size and variations in treatment scheduling. Although we aimed to treat all patients with relugolix for a total of 4-6 months with initiation 2 months prior to SBRT, there was heterogeneity in the timing of initiating prostate SBRT. Due to the small sample size, we did not examine whether there were differences in outcomes depending on the timeliness of SBRT. We employed a short course of administration, and adherence may not be as high with a long course (21, 24). Additionally, the SMAQ is not validated for hormonal agents, and the SMAQ did not assess medication concerns associated with non-adherence (i.e., necessity, harmfulness, etc.). Due to high levels of castration, we could not definitively correlate results with an objective measure of adherence.

Relugolix allows for high rates of castration and drug adherence when combined with SBRT. Monitoring drug adherence during treatment may allow for prompt detection of non-adherence and timely intervention. Future studies should focus on how to optimally incorporate the SMAQ into patient management.