Prescription pattern of abiraterone in Brazil - a survey of medical oncologists

Prostate cancer is the second most common cancer in men worldwide. It is estimated that by 2030, 1.9 million men will be diagnosed with prostate cancer globally, with around 50.000 deaths. In Brazil, 97,000 new cases were diagnosed in 2020, with approximately 18,000 deaths.1

Since the 1950s, androgen deprivation therapy (ADT) is the backbone of treatment for metastatic disease.2 However, the duration of response to ADT is often limited and almost all patients will experience disease progression to metastatic castrationresistant prostate cancer (mCRPC) at some point of their course. The two most important mechanisms leading to castration resistance are the androgen receptor (AR) hyperexpression and incomplete blockade of AR-ligand production.3

Abiraterone acetate (AA) was developed in the 1990s and it is a potent selective inhibitor of CYP17A1, member of p450 cytochrome family and involved in androgen production. AA mechanism of action is based on reducing androgen synthesis, including at the tumor and microenvironment level, and at the adrenal gland.4,5 AA was approved by the Food and Drug Administration (FDA) in 2012 initially to mCRPC, based on the phase III study COU-AA-301, which compared AA to placebo in patients already exposed to docetaxel and demonstrated that AA was associated with an increase in overall survival (OS).5 The label recommended dose of AA is 1,000mg orally to be taken fasting in association with prednisone 5mg, orally twice daily.

Since the initial AA approval, several indications emerged, including mCRPC pre-docetaxel,6 in castration sensitive prostate cancer (CSPC),7,8 and more recently in localized nonmetastatic high risk prostate cancer9 in combination with ADT and radiation. Of note, akin to its first approval, for all indications the dose of 1,000mg/daily was maintained. Furthermore, in addition to AA, other novel antiandrogens (NAA) such as enzalutamide, darolutamide, and apalutamide, of different mechanism of action (antagonists of the androgen receptor) have also been approved for similar indications.10 11 12

Despite the dose of 1,000mg fasting has been chosen as recommended phase 2 dose (RP2D), the safety and pharmacokinetics of AA when coadministrated with food was also tested.13 When administered with a low-fat meal, AA absorption is increased 5-7 fold. Hence, a dose of 250mg with lowfat meal yields a similar drug exposure in comparison to the standard dose of 1,000mg fasting. Moreover, according to the drug label, a high fat meal leads to a 10-17 times increase in drug concentration.14

In 2018, Szmulewitz et al.15 conducted a non-inferiority prospective phase II trial comparing the standard dose of AA (1,000mg/daily) with 250mg/daily with low-fat meal and showed a similar decrease in PSA levels, a similar progression free survival (PFS) and a similar decrease in dehydroepiandrosteronesulfate (DHEA-S) (pharmacodynamic marker of AA activity) between the two arms. Based on this trial, the National Comprehensive Cancer Network (NCCN) included AA low-dose with food as an acceptable alternative to men with prostate cancer.16 The use of AA 250mg with food implies in a 75% cost-savings in comparison to the label-dose.

In Brazil, AA at the label dose is not affordable to over 75% of patients treated under the public national health plan (Sistema Único de Saúde – SUS). However, a lower dose of 250mg with food may fit into the budget and has already been prescribed at some Brazilian centers.17 There are no data in regards to the pattern of prescription of AA in Brazil, and whether prescribers (medical oncologists and urologists1 are aware of the low-dose AA data, and what are their thoughts in regards to the prescription of such regimen in their practices. We undertook a survey to investigate the pattern of prescription of AA in Brazil, including the uptake of AA low-dose.

After ethical approval (CAAE 59172022.1.0000.5415), a survey was created utilizing the questionnaire tool of the Research Electronic Data Capture (REDCap) of Hospital de Base.18,19 We asked fourteen questions, including prescribers' demographics, and awareness about the literature supporting AA low-dose – Appendix 1. Medical oncologists and urologists treating patients with metastatic prostate cancer were eligible to participate. The survey was distributed through a social media platform (WhatsApp) to approximately 500 prescribers (WhatsApp groups) – medical oncologists and urologists – at two separate dates: September 5^th, 2022, and September 26^th, 2022.

In total, 48 prescribers responded the survey - 45 medical oncologists and 3 urologists. Because of the small sample size, we decided to exclude urologists’ response from the statistical analysis. The median age of respondents is 35.5 years old and 55.6% are female 'Table 1). Thirty-nine (86.7%) of respondents work at an academic institution (affiliated to a medical school or with a residency program) and 73.3% practice in both public and private healthcare systems (Table 1). Most respondents completed their final specialty within the last 5 years (51.1%) (Table 1). Regarding the volume of prostate cancer patients in their practices, participants responded that 25% (SD 16) of their workload is comprised of patients with prostate cancer (Table 1).

When asked if they had read the phase II study by Szmulewitz et al. (2018),15 86.4% of respondents answered “yes” – Table 1. Eighty percent were aware of NCCN recommendations acknowledging the prescription of low-dose AA – Table 1. In terms of willingness to prescribe AA low-dose, 90.9% versus 25% would prescribe AA low-dose in the public (SUS) and private healthcare systems, respectively (Figure 1). Twenty-two medical oncologists (50%) are already using AA low-dose in their practices (Figure 1). Among those who would not prescribe AA lowdose, 50% justified that are not confident on the data supporting AA low-dose, and 50% because AA-low dose is not the standard of care.

In our surveyed population, most prescribers were knowledgeable about data supporting the use of AA low-dose. Moreover, over 90% of medical oncologists were willing to prescribe AA low-dose for patients treated under the Brazilian national health plan (SUS) — where resources are scarcer and treatment options are limited — and half were already using AA low-dose as part of their arsenal for prostate cancer treatment. As expected, physicians who had read the article by Szmulewitz et al.15 and who were aware of the incorporation of AA-low dose as an option by NCCN guidelines were more likely to prescribe AA-low dose in their practices.

Our survey share similarities with the work conducted by Patel et al. (2020)4 interrogating AA prescription patterns in India. In their study, of 118 respondents, 58.8% were aware of NCCN’s recommendation of AA-low dose and 6.8% were prescribing AA low-dose in their practices. While our numbers are more encouraging, most physicians we surveyed were from academic centers, and were younger than the average Brazilian oncologists (35.5 vs. 45.7 years old).20 Furthermore, our population was acquired by convenience through the distribution of the survey in WhatsApp groups. We speculate that our respondents were more likely to be update with the oncology literature and therefore aware of data on AA low-dose, which is not necessarily generalizable to all (or even most) oncologists from Brazil. In addition, the longer time between the Szmulewitz et al.15 publication and our work in comparison to Patel’s et al.,4 may have had impact in the observed differences, with more time available for spreading the message of the research findings.

While most of our surveyed oncologists would prescribe AA low-dose in the public health system (SUS), only 50% had already adopted AA low-dose in their practices. The reasons for that are likely multifactorial and are beyond the scope of this project. In a recent literature review, concerns about erratic exposure of AA under diverse dietary patterns are amongst potential reasons.21 In lowmiddle income countries (LMICs), food insecurities are always an important concern and need to be taken in consideration before treatment planning. Nevertheless, regardless of the motives, implementation science is needed to improve AA low-dose access to Brazilian patients.

Lower doses of AA can result in up to 75% cost savings which is highly relevant to LMICs such as Brazil. Several data support the use of AA at a lower dose with food.13,14,16,17,22 In addition to Szmulewitz et al.15 trial, a retrospective study conducted at the Princess Margaret Cancer Center showed no statistically significant differences in PSA response rate, biochemical progression free survival (bPFS), and OS in patients with mCRPC between who received AA low-dose (250mg or 500mg) versus the standard dosing.22 In Brazil, Zucca et al. (2020),17 reported results of 49 patients with mCRPC treated with AA low-dose post docetaxel. They found a PSA response rate ≥50º/o in 51% of patients which is in keeping with data from the COU-AA-301 trial.5

The dosing conundrum of oncology agents has been the subject of recent scrutiny by several groups including the Optimal Cancer Care Alliance (OCCA — https://optimalcancercare.org/)²⁴ and even the FDA.23,24 Project Optimus is an FDA-led initiative stimulating a more comprehensive dose exploration strategy to oncology agents during their early phase of development, before moving to the formal assessment of efficacy endpoints. It has been postulated that most oncology treatments, particularly oral tyrosine kinase inhibitors (TKI) and monoclonal antibodies, are overdosed at their currently approved label doses. Furthermore, the role of food exposure for oral agents has systematically been relegated in drug development and is often not reported (when not conducted) in phase 1 trials. The Methodology for the Development of Innovative Cancer Therapies (MDICT) guidelines recommends that novel agents should consider the initial dosing with food unless there is strong evidence that food may importantly impair absorption.25

In reference to corticosteroid therapy, our study showed AA is most frequently prescribed (41.9%) in association with prednisone 5mg twice daily regardless of the treatment scenario, in line with the prescription patterns of to the pivotal trials COU-AA-301 and COU-AA-302(5,6) and in opposition to the LATITUDE trial that used 5mg/daily to CSPC.26 The strategy of using 5mg twice daily is also supported by the work of Attard et al. (2019),27 suggesting that in comparison to other corticosteroid treatment possibilities, 5mg bid is more efficient in avoiding excess of mineralocorticoids. Regarding the switch from prednisone to dexamethasone upon progression, only a minority of respondents adhere to this practice. Nevertheless, data suggests that up to 30% of patients who progress on AA and prednisone can experience a PSA decrease simply by switching corticosteroids.28 While little is known about the true impact of this practice in survival, this is a convenient and well tolerated approach that can yield some additional time to patients on AA without switching to a new line of treatment or even exclusively palliative care.

We acknowledge several limitations of this study. First, the response rate of our survey was low, with only 48 respondents. Furthermore, only 3 urologists responded to the survey making our findings most applicable to medical oncologists. Secondly, our sample was acquired by convenience which by default induces biases in interpretation of results. For instance, our population was mostly constituted of physicians working at academic centers, who are more likely to be updated with medical literature. We hypothesize that awareness of AA low-dose is lower than what we found in this survey. Finally, our limited sample size prevented performing multivariable analyses.

It is important to discuss AA low-dose in Brazil and other LMICs, particularly in settings where the standard treatment is unavailable due to cost constraints. Larger studies (e.g., phase 3 trials) investigating AA low-dose are unlikely to occur as these are off the agenda of pharmaceutical industries.21 Nevertheless, considering the increased accessibility and the economics involved in using AA-low, we advocate for the implementation of AA low-dose in a near-equivalence fashion.29

This survey study showed a trend towards Brazilian medical oncologists prescribing AA lowdose. However, only half of the respondents already use AA-low in their practices. We advocate for broader use of AA low-dose, increasing accessibility.

No funding was used for this work.