Expert Review of Anticancer Therapy

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iery20

Abiraterone acetate in combination with

prednisone in the treatment of prostate cancer:
safety and efficacy

Cécile Manceau , Loic Mourey , Damien Pouessel & Guillaume Ploussard

To cite this article: Cécile Manceau , Loic Mourey , Damien Pouessel & Guillaume Ploussard
(2020): Abiraterone acetate in combination with prednisone in the treatment of prostate cancer:
safety and efficacy, Expert Review of Anticancer Therapy, DOI: 10.1080/14737140.2020.1785289

To link to this article: https://doi.org/10.1080/14737140.2020.1785289

Accepted author version posted online: 18

Jun 2020.

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 Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Expert Review of Anticancer Therapy

DOI: 10.1080/14737140.2020.1785289
Abiraterone acetate in combination with prednisone in the treatment of prostate cancer: safety
and efficacy

*Cécile Manceau 1, Loic Mourey 3, Damien Pouessel 3, Guillaume Ploussard 2

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1. Department of Urology, CHU-IUCT Oncopole, Toulouse, France

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2. Department of Urology, La Croix du Sud Hospital, Quint Fonsegrives, France
3. Department of Medical Oncology, Institut Claudius Régaud, IUCT Oncopole, Toulouse, France

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*Corresponding author: Cecile.manceau2@gmail.com

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 Abstract

Introduction: Metastatic prostate cancer is a life-threatening disease and an important public health

concern with prevalence rates varying drastically between high- and low-income countries.

Androgen-deprivation therapy alone has been the first-line treatment option for decades,

temporarily controlling disease until invariable tumor regression. At the castration-resistant stage,

metastatic disease becomes lethal. In recent years several new treatments, including second-

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generation hormone therapies, have proven to be life-prolonging in metastatic castration-resistant

prostate cancer, and at an earlier hormone-sensitive stage. Abiraterone acetate in combination with

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prednisone was the first approved hormone therapy demonstrating survival benefit, and represents,

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to date, an alternative or a second-line treatment after taxane-based chemotherapy, in addition to

androgen-deprivation therapy, in hormone sensitive and metastatic castration-resistant prostate

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cancer.

Area covered: We performed a literature review of papers from 2012 to 2020 using PubMed, Web of
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Science, and Embase searching for the safety and efficacy of abiraterone acetate in prostate cancer

management. Search results were limited to phase III-IV trials and post-hoc analysis of Phase III trials
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evaluated Abiraterone acetate in the English language.

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Expert opinion: This literature review confirms the role of abiraterone acetate in the therapeutic
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landscape with well-proven safety and efficacy, demonstrated in trials and post-approval studies.
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Keywords: Abiraterone acetate, second-generation androgen receptor inhibitor, metastatic

resistant-castration prostate cancer, metastatic castration-sensitive prostate cancer; prostate cancer
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 Article highlights

- Abiraterone acetate is a second-generation hormone therapy, orally available with a good

safety profile and overall survival benefits in metastatic prostate cancer

- Abiraterone acetate is an improvement for metastatic prostate cancer prognosis and patient

well-being

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-

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Abiraterone acetate is a less aggressive alternative to taxane-based chemotherapy

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 1. INTRODUCTION

Prostate cancer (PCa) is the second most common cancer worldwide and the fifth leading cause of

death from cancer among men [1]. Metastatic prostate cancer still represents a lethal disease

despite strong developments in the therapeutic arsenal during the last decade. Since the works of

Huggins and Hodges [2], androgen suppression has become the cornerstone of metastatic stage

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treatment allowing control of disease until invariable progression to the castration-resistant stage.

Recent years has seen significant changes for the treatment of advanced and metastatic prostate

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cancer with the approval of several new drugs, including chemotherapy (docetaxel, cabazitaxel),

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bone-targeted therapies (radium-223), vaccination (sipuleucel-T), and new generation hormone

therapies (abiraterone acetate, enzalutamide). All these drugs have proven to be life-prolonging in
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randomized controlled trials.

Actually, abiraterone acetate (AA) in combination with prednisone and luteinizing hormone-releasing
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hormone (LHRH) agonists or antagonists is a recommended treatment option in men with metastatic

castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer

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(mCSPC).
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The aim of this literature review was to present strong evidence data about the efficacy and safety of
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abiraterone acetate including its mechanisms of action and side effects, in both CRPC and CSPC

stages.
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 2. MECHANISM OF ACTION

Firstly, the androgen receptor (AR) has been known for many years to be a regulator in PCa from

disease development to progression and treatment [2]. Androgen deprivation therapy (ADT) with

LHRH analogs and anti-androgens allow a suppression of circulating testosterone levels, blocks

transcriptional activity of AR and temporary tumor regression. Then, there is an AR reactivation in

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response to ADT with new AR signaling. Multiple mechanisms have been identified to explain this

phenomenon including AR gene mutation, overexpression, AR splice variants expression and the

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expression of transcriptional co-activators overexpressing androgen dependent genes [3]. Moreover,

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intraprostatic cells can be a significant source of androgen under the selective pressure of endocrine

therapy [4].
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AA is a new molecular entity for blocking AR expression [5], orally available.

AA is converted in vivo to abiraterone which is a selective and irreversible 17 α-hydroxylase/C17,20

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lyase (CYP17A1) inhibitor.

CYP17A1 is an enzyme expressed in steroidogenic tissue like testes and adrenal cortex. It’s also
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expressed in prostatic tumor tissue. This enzyme is involved in conversion of cholesterol to the
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androgen precursor and steroid hormone synthesis. The generation of glucocorticoid such as cortisol
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requires 17 α-hydroxylase as it converts pregnenolone and progesterone to 17-hydroxypregnenolone

and 17-hydroxyprogesterone. So, 17 α-hydroxylase deficiency impairs glucocorticoids production,

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pregnenolone and progesterone increase. The decrease in cortisol levels includes a compensatory
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increase in adrenocorticotropic hormone (ACTH) and the increase in pregnenolone and progesterone

is treated to form mineralocorticoids [6]. Prednisone is associated to compensate cortisol reduction

due to 17 α-hydroxylase inhibition, therefore, decreasing the mineralocorticoid excess [6] (Fig 1).

Along with 17 α-hydroxylase, C17,20 lyase is required for the production of androgenic sex steroid.

Pregnenolone to 17-hydroxypregnenolone is converted by 17 α-hydroxylase, C17,20 lyase next

converts 17-hydroxypregnenolone to dehydroepiandrosterone (DHEA), a precursor of

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 dihydrotestosterone. So, abiraterone inhibits synthesis of dihydrotestosterone (DHT) and reduces

production of androgens in the tumor tissue [7].

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3. MAIN SIDE EFFECTS

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Mechanisms of action of AA explain some adverse effects like excess mineralocorticoids and

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adrenocortical insufficiency, but clinical studies and post-approval studies identified other adverse

effects like hepatotoxicity and cardiac disorders. Prednisone association and glucocorticoid adverse
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effects were also studied.
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a. Mineralocorticoid excess

As pregnenolone and progesterone increase, so does mineralocorticoids which may cause

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hypertension, hypokalemia, and fluid retention. This is why patients must be monitored at least once
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a month. Hypertension control and hypokalemia correction should be used, if necessary, during
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treatment.

For mCRPC, patients received AA with prednisone at a dose of 5 mg orally twice daily [8]. For mCSPC,
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STAMPEDE and LATITUDE studies were designed with prednisone at a dose of 5 mg orally once a day
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[9,10]. Mineralocorticoid side effects were more frequent compared to COU301 and COU302 trials

(with prednisone at a dose of 5 mg twice a day) but this increase could be explained by lower steroid

doses but also longer exposure to AA.

Grade 3-4 hypertension were observed in 2 to 10% of patients grade 3-4 hypokalemia in 3-10%, and

fluid retention in 1-3% [9–12]. Tension, hypokalemia and fluid retention have to be monitored at

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 least once a month. These adverse events can easily be managed medically by patient monitoring.

For example, oral potassium supplementation, anti-hypertensive agent.

b. Adrenocortical insufficiency

Prednisone is associated with AA to compensate cortisol reduction due to 17 α-hydroxylase

inhibition. However, steroid interruption or stress or infection could lead to an adrenocortical

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insufficiency. Adrenocortical insufficiency has rarely occurred (0,3% in clinical studies according to

the prescribing information) highlighted by two cases in literature [13]. It was reported when

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patient interrupted prednisone along with abnormal stress or infection. During AA treatment in

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combination with prednisone, special monitoring is not recommended, increased dosage of

corticosteroids may be indicated before, during and after stressful situations.

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c. Hepatotoxicity
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AA can be associated with hepatic toxicity and aminotransferase level elevation. In clinical trials 6%

of patients were reported to have grade 3-4 hepatic disorders without deaths but patients displayed
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fulminant hepatitis, acute liver failure and deaths in post-approval studies. These disorders appeared
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typically during the first 3 months after starting treatment. Aminotransferase and bilirubin levels
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have to be measured prior to starting treatment and every two weeks for the first three months of

treatment and monthly after. Hepatotoxicity may lead to interruption, reduced dose level, or, to
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permanently discontinued treatment.

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d. Cardiac disorders

Cardiac disorder in AA plus prednisone versus prednisone-only groups were rare. The most

frequently observed cardiac events were grade 1 and 2 tachycardia events and grade 3 or lower

atrial fibrillation events. Moreover, hypokalemia can lead to heart rhythm disorders. Recent meta-

analysis included prospective studies and showed that use of new hormonal agents was associated

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 with an increased risk of all-grade (Risk Ratio (RR), 1.36) and high-grade (RR, 1.84) cardiac toxicity

[14].

Patients with severe heart failure NYHA III-IV or with left ventricular ejection fraction <50% were

excluded from clinical trial, so can’t safety be defined. Post-approval studies identified torsade de

pointe and QT prolongation in patients with hypokalemia or had underlying cardiovascular condition.

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e. Glucocorticoid adverse effects

The use of glucocorticoid replacement therapy with prednisone low dose, may restore normal

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physiology while minimizing adverse effects. It compensates for the abiraterone-induced reduction

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in serum cortisol, normalizes the abiraterone-induced rise in ACTH [6,12]. With this low dose

compared with the dose used to treat autoimmune or cancer disorders, the mineralocorticoid
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activity of prednisone is minimal. The two most common any-grade corticoid adverse effect were

hyperglycemia (7.8%), and weight increase 3,9%. Other any-grade AEs occurred in 1% of patients
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[15].The cumulative dose over a prolonged treatment period may alter bone metabolism,

hyperglycemia, diabetes, immunosuppression, muscle sickness, negative effect on mood and

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cognitive function.
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f. Abiraterone in elderly (≥75 Years)

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In clinical trial, elderly patient in both arms of the study (with and without AA) had higher rates of
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fluid retention and cardiac disorder, specific adverse effect were similar between age subgroup

[16,17].

A recent, multicentre, phase IV study has confirmed the safety of abiraterone acetate in mCRPC [18].

In this study, adverse effects and impacts on quality-of-life have been prospectively assessed in

comparison with enzalutamide, another new generation hormone therapy. Patient-reported

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 outcome items such as cognitive impairments and fatigue were significantly in favour of abiraterone

versus enzalutamide without any treatment-related death. Thus, real-world, post-approval studies

confirmed the mid-term safety of abiraterone acetate and its potential advantages compared with

other hormonal therapies.

AA is well tolerated with adverse effects being predominantly grade 1 or 2. Principal toxicities can be

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successfully medically managed with patient monitoring and were generally reversible. AA was not

associated to any adverse hematological events.

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Good tolerance was an important point for using this molecular entity for pathologies that were

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previously treated with cytotoxic chemotherapy only.

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 5. DRUG INTERACTION

AA involves hepatic metabolism and liver enzymes belonging to the cytochrome P450 (CYP450)

family. In vitro studies showed that CYP1A2, CYP2C8, CYP2D6 are mainly inhibited by AA and CYP2C9;

CYP2C19 moderately. These enzymes play a role in metabolism of other drug classes like analgesics,

antidepressants, antidiabetics, lipid-lowering drug and cardiovascular drugs (beta blockers) [19].

CYP2D6 and CYP2C8 inhibition was shown in clinical studies [20,21], but CYP1A2 substrates were not

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increased [20]. CYP2D6 inhibition can decrease analgesic effect of codeine, antidepressant drugs

(paroxetine and tricyclic antidepressant) and amitriptyline. Additionally, CYP2C8 inhibition can

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increase insulinotropic agent activity and AA increases the AUC of pioglitazone in healthy volunteers

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[21]. Yet no direct evidence has been provided between AA and repaglinide so this co-administration

should be monitored and switched to alternative recommended drugs in case of hypoglycemia.

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Abiraterone is metabolized in the liver in inactive compounds by CYP3A4. CYP3A4 inducers (like

rifampicine) decrease AA exposure by half [22]. In contrast, CYP3A4 inhibitors (like ketoconazole)
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have no clinically significant impact on abiraterone exposure.

Post-approval studies didn’t report major problems but co-administration with analgesics,
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antidepressants, antidiabetics, lipid-lowering drug and cardiovascular drugs should be closely

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monitored specifically for codeine, tricyclic antidepressant, pioglitazone, repaglinide, and CYP28
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statin substrate. These co-administrations must be considered when choosing among the different

new generation hormonal agents.

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 6. METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

AA in combination with prednisone is indicated for the treatment of patient with metastatic

castration-resistant prostate cancer (mCRPC).

Such recommendations have been based on two randomized, placebo-controlled, multinational,

phase 3 studies, the COU-AA-301 and the COU-AA-302 studies.

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COU-AA-301 was a multinational, randomized, double-blind, placebo-controlled, phase 3 study

including patients with mCRPC progression previously treated with docetaxel, with an Eastern

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Cooperative Oncology Group (ECOG) between 0 and 2 (post-docetaxel setting).

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COU-AA-302 was a multinational, placebo-controlled, double-blind, randomized phase 3 study

including patients with asymptomatic or mildly symptomatic mCRPC who had not received previous
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chemotherapy and belonging to ECOG 0 or 1 (pre-docetaxel setting).

Both trials randomized patients to receive AA + prednisone twice a day, or placebo + prednisone
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twice a day. Both studies showed an improvement in overall survival (OS) with AA independent of

the chemotherapy status.

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In the final analysis of COU-AA-301 including 1195 patients. With a median follow-up of 20.2 months
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[11], median overall survival for the abiraterone group was longer than in the placebo group with a
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median OS increasing of 4.6 months for patients with mCRPC who had progressed post-docetaxel.

Median time to prostate specific antigen (PSA) progression increased to 1.9 months, with median
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radiologic progression free survival (rPFS) set at 2 months. The survival benefit seen with abiraterone
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was consistent for the majority of subgroups but not for ECOG 2 patients, for patients who received

docetaxel for 3 months or less, and for patients who received 2 prior lines of chemotherapy at study

entry. In the subset of visceral diseases, the small sample size does not allow to conclude for the

primary endpoint but median OS was 12.9 months with AA and 8.3 months with prednisone alone

and rPFS, showing a statistical significance [23].

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 Secondary analysis observed an improvement in patient-reported fatigue intensity [24] and benefits

in patient-reported health-related quality of life (HRQoL) along with increasing delay in HRQoL

deterioration [25]. Bone-related symptoms (patient-reported pain palliation, delay in pain

progression, and delayed time to skeletal-related events) were favorably affected by AA treatment

[26].

Elderly patients derived clinical benefits similar to younger patients with increased hypertension,

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hypokalemia and cardiac disorders yet these observations were similar in the placebo group [16].

In the final analysis of COU-AA-302 including 1088 patients with mCRPC who had not received

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previous chemotherapy and with a larger median follow up of 49.2 months, median OS for the

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abiraterone group was longer than in the placebo group with a median OS increasing by 4.4 months

[27]. Intermediary analysis with median follow up of 22.2 months did not find significant difference in
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OS while there was a significant difference in rPFS [28]. Subgroups analysis in intention to treat

population didn’t find significant difference in OS for patients ECOG 1, pain (brief pain inventory-
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short form ≥2), age <65 years or presenting a high baseline PSA. Qualitatively, we conclude that

patients initially receiving prednisone alone subsequently received AA plus prednisone as crossover
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per protocol (17%) or as a subsequent therapy (27%). Moreover, baseline serum PSA, bone
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metastases at baseline, and age were all significant prognostic factors for overall survival in
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multivariate analysis, only ECOG performance status score was not.

Regarding the co-primary endpoint, rPFS, with median follow up of 27.1 months, AA doubled time to
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progression from 8.2 to 16.5 months [29]. Secondary analysis confirmed this rPFS improvement in all
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subgroups. Patients with mCRPC who had not received previous chemotherapy treated by AA also

reported statistically significant improvements in pain interference and functional status [29]. As

COU-AA-302, OS benefit were persistently for older patients [17].

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 To conclude, AA is a recommended, life-prolonging, well-tolerated, treatment option in mCRPC

patients before or after taxane-based chemotherapy. These encouraging results led to study AA at an

earlier stage for metastatic high-risk castration-sensitive prostate cancer.

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 7. METASTATIC HIGH-RISK CASTRATION-SENSITIVE PROSTATE CANCER

The benefit of AA in combination with prednisone was then investigated in two phase III trials for

patients with metastatic castration-sensitive prostate cancer (mCSPC).

LATITUDE is a randomly, double-blind, placebo-controlled, phase 3 trial [30]. Patients included were

newly diagnosed mCSPC patients with two of the three following high-risk factors associated with

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poor prognosis (a Gleason score of 8 or more, at least three bone lesions and the presence of

measurable visceral metastasis) and ECOG 0-2. A total of 1199 patients were randomly assigned in a

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1:1 ratio to receive ADT + AA + prednisone once a day versus ADT + dual placebo.

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Final analysis with median follow-up of 51.8 months, showed a significantly longer OS (53.3% vs

36.5%) in the AA plus prednisone group with the median length of rPFS (the second primary
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endpoint) being 33 months in the abiraterone group and 14.8 months in the placebo group. This

benefit was consistent for the majority of subgroups.

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Secondary analysis reported an improvement regarding time to pain progression (47.4 vs 16.6

months) and time to skeletal related events. The addition of abiraterone acetate delayed subsequent
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prostate cancer therapy as well as the time of chemotherapy initiation. An exploratory analysis
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assessing the progression-free survival on subsequent treatment (named PFS2) also showed a
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significant PFS improvement in the abiraterone arm suggesting an advantage for early abiraterone

treatment.
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Health-related quality of life (HRQOL), progression of pain, prostate cancer symptoms, fatigue and
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functional decline were also evaluated. There were improvements of pain, fatigue symptoms and

overall HRQOL by using abiraterone acetate. Patients in the abiraterone group had longer median

time to worst pain intensity progression, worst fatigue intensity progression and functional

deterioration status [20].

STAMPEDE is a randomly, open label, multi-arm, multistage controlled trial including locally

advanced or metastatic prostate cancer patients who initiated for the first time ADT [31]. The

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 primary aim of this multi-arm trial was to test the benefit of the addition of further treatment with

ADT to improve OS. Concerning the abiraterone acetate study in CSPC patients, 1917 patients were

randomized, including newly diagnosed high-risk patients with at least two of the three high-risk

factors (T3-T4 stage, PSA ≥40 ng/mL, Gleason grade ≥ 8), nodal disease, metastatic prostate cancer

and previously treated relapsing patients (surgery or radiotherapy with <12 months of hormone

therapy) with at least one of the four high-risk factors (PSA ≥4 ng/mL and increasing with a doubling

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time of <6 months; PSA ≥20 ng/mL; nodal invasion or, metastatic disease). Local radiotherapy was

mandated for patients with node-negative, nonmetastatic disease and encouraged for those with

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positive nodes. A total of 95% of patients had newly diagnosed disease and 52% had metastatic

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disease.

With a median follow up of 40 months, there was an overall survival advantage for the AA + ADT
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group compared with ADT alone, with a hazard ratio of 0.63 (0.75 in patients with nonmetastatic

disease and 0.61 in those with metastatic disease).

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The benefit was the same for the intermediate primary outcome and failure-free survival (including

death and progression) where there were less treatment failure events in the AA group compared
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with those reported in the ADT alone group (hazard ratio 0.29). The latter included patients from the
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whole cohort in both metastatic and nonmetastatic subgroups [32]. However, differences were more
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important in the metastatic subgroup.

Important differences of patient selection have to be highlighted between STAMPEDE and LATITUDE
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trials. The LATITUDE trial only included de novo, metastatic CSPC patients who exhibited high-risk
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cancer, as defined by Gleason score, site and number of metastases. The STAMPEDE trial was

dedicated to every patient candidate for ADT, including those with high-risk but nonmetastatic

cancer and those with low-risk mCSPC. Sub-group analyses in the STAMPEDE trial tended to support

the benefit of AA, even in the non-LATITUDE-like patients [33]. These main studies are summarized in

Table 1.

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 8. CURRENT RECOMMENDATIONS

With strong evidence, national and international guidelines currently recommend AA plus

prednisone as treatment options for mCRPC and mCSPC patients.

The European EAU-ESTRO-SIOG guidelines [34] recommend AA plus prednisone with castration for

the first line treatment of metastatic prostate cancer to all patients whose first presentation is M1

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disease and who are fit enough to receive this treatment (Level A). For mCRPC, AA can be offered as

first and second line treatments. Physician’s choices should be based on performance status,

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symptoms, comorbidities, location, extent of disease, patient preference and previous treatment.

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French national committee guidelines [35] recommend that with grade A, a combination of evidence

level AA, prednisone and castration be used as first line treatment of metastatic prostate cancer,
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especially in high risk populations. For first line mCRPC, no predictive factors have been identified to

recommend second generation hormonotherapy rather than taxanes. With a grade B level of
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evidence, second generation hormonotherapy is recommended for asymptomatic or mildly

symptomatic patients without visceral metastasis.

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American urological association (AUA) guidelines [36] extended the AA recommendation (grade C) to
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non-metastatic CRPC patients at high risk of developing metastatic disease who do not want, or
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cannot have one of the standard therapies (enzalutamide or apalutamide) and are unwilling to

accept surveillance. This recommendation based on superior survival benefits was shown in
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metastatic CRPC and metastatic high-risk castration-sensitive prostate cancer but is not FDA-
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approved for non-metastatic patients due to a lack of significant long-term data in this specific

population.

In first line mCRPC treatment, AA is recommended for asymptomatic or mildly symptomatic mCRPC

(grade A), symptomatic with good performance status (grade A) and with grade C for poor

performance status. After docetaxel, AA can be used for patients with good performance status

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 (grade A). Expert opinion presents AA as an alternative for selected patients with poor performance

status who are not eligible for supportive care only.

Thus, consensus has been reached between different guidelines regarding the use of AA plus

prednisone in metastatic prostate, with strongest evidences pointing to asymptomatic or mildly

symptomatic mCRPC and high-risk mCSPC.

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 9. RESISTANCE MECHANISMS

The natural evolution of the metastatic prostate cancer is often marked by an initial response phase

to abiraterone followed by relapsed disease progression in long term patients and ultimately results

in a disease non-responsive to abiraterone. However, some CRPC patients exhibit primary resistance

where commencement of AA treatment is not associated with decreasing PSA, other clinical and/or

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imaging progression. This phenomenon was reported in less than 10% of chemotherapy naïve

patients with mCRPC [27] and less than 40% of patients with mCRPC after chemotherapy [8]. As

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resistance mechanisms to CYP17A1 inhibitor are still poorly understood, AR activity appears to be

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restored. Animal models, tumor biopsy mRNA or liquid biopsy of patients who had developed

resistance to CYP17A1 inhibitor were studied. A few mechanisms were suspected; progesterone
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driven mutation, AR mutation, amplification, AR enhancer mutations, AR splice variants [37], AR

activation by exogenous corticosteroids and steroids precursors upstream of CYP17A1, androgen

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biosynthesis pathway upregulation, glucocorticoids and glucocorticoid receptor overexpression [3].

Mutations in the binding domain of the AR ligand might be one of these mechanisms, resulting in
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permanent activation of the AR without the ligand [38]. One of the most important examples of AR
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permanent activation is the AR splice variant 7 (AR-V7) which is prevalent in CRPC. This splice variant
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is the result of an abnormal splicing of intronic sequences and encodes a truncated AR protein

[39,40]. The latter has a transactivating domain and lacks a ligand binding domain. So, the AR is
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unable to bind ligand and is permanently activated. Amplification of this variant is one cause for the
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abiraterone escape mechanism. AR-V7 messenger RNA can be detected reliably from circulating

tumor cells (CTC) and different methods can be used to detect AR-V7. A clinical study showed, upon

performing a RT PCR for mRNA detection of this splice variant in CTC, that AR-V7 was associated with

resistance to abiraterone and enzalutamide. AR-V7 positive patients had no, or less PSA responses

and no any appreciable clinical benefits [41,42]. However, this AR splice variant does not explain all

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 of the mechanisms of resistance as patients negative for AR-V7 did not respond to abiraterone and

enzalutamide [43].

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 10. ONGOING STUDIES

Numerous studies are ongoing to keep on evaluating efficacy, safety, and tolerability of AA, alone or

in combination, in special populations.

Other studies have been designed to explore biomarkers predictive for abiraterone response. In

addition, combinations with chemotherapy, olaparib (PROpel trial), radiotherapy (ARTO trial),

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different sequences and re-challenge are being tested for metastatic prostate cancer.

Studies are underway to extend the indication to advanced non-metastatic prostate diseases

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including a prospective, multicenter, phase II trial in men with non-metastatic, castration-resistant

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prostate cancer (IMAAGEN trial), or neo-adjuvant use for patients diagnosed with localized high-risk

prostate cancer prior to radical prostatectomy or radiotherapy.

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Given the availability of other drugs targeting the androgen-receptor pathways such as

enzalutamide, apalutamide, and darolutamide, the debate concerning the ideal sequence and the
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potential usefulness of combination therapies remains. Few studies are currently available exploring

these two questions. The phase II PLATO study has evaluated the interest of combining abiraterone
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acetate with enzalutamide as mCRPC second-line hormonal therapy in patients experiencing

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progression after enzalutamide as first-line treatment [44]. The same study showed that switching
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enzalutamide with abiraterone did not produce a significant difference in disease control. No benefit

was provided by combining new generation therapy.

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Another combination trial is ongoing, the ACIS trial, assessing the potential benefit of the association
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apalutamide plus abiraterone (compared with abiraterone acetate alone) in terms of rPFS in

chemonaive mCRPC patients. Results are pending and expected in 2021.

The difference of efficacy between abiraterone acetate then enzalutamide versus enzalutamide then

abiraterone has been assessed in a phase II trial in mCRPC patients (Khalaf, Lancet Oncol 2019).

Findings tended to support the use of abiraterone acetate for first line treatment, as the second PSA

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 progression was reached after a greater delay for the sequence of abiraterone followed by

enzalutamide than with the opposite treatment sequence.

Different approaches attempting to delay acquired resistance to AA are also being studied including

combination therapies and ideal sequences, but a potential strategy after resistance would be to

supplement patients with testosterone (RESTORE study).

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Main studies used Zytiga ©, but generic versions of AA have been approved by the FDA after

bioequivalence demonstration [45] and Zytiga’s exclusivity expires on February, 2021.

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Other conditions could be targeted. This is the case in preliminary studies regarding the management

of Cushing's syndrome in patients with adrenocortical Carcinoma (ABACUS), the molecular apocrine
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breast cancer (AMA) treatment and the androgen reduction in congenital adrenal hyperplasia.
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 11. CONCLUSION

AA is a second-generation hormone treatment which is a standard molecular entity for blocking

androgen receptor expression, acting as a selective and irreversible CYP17A1 inhibitor. AA inhibits

the conversion of cholesterol to an androgen precursor and steroid hormone synthesis in

steroidogenic tissue. Its mechanism of action explains the decrease in cortisol levels and the

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necessity of concomitant prednisone supplementation to reduce adverse effects. AA presents a good

safety profile with the main serious side effects including hepatotoxicity and cardiotoxicity, requiring

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close monitoring upon treatment initiation.

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Several large-scale phase III trials showed significant overall survival benefits in mCRPC and mCSPC

patients leading to a recent change in prostate cancer treatment recommendations. Future studies
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should focus on the identification of predictive biomarkers of disease response and early resistance,

at late stages with the potential for combination therapy.

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 12. EXPERT OPINION

Prostate cancer remains an important life-threatening public health issue given its prevalence and its

related mortality. At a metastatic stage, disease is not curable and androgen suppression has proven,

for decades, its importance in the castration sensitivity of prostate cancer. Androgen suppression by

orchiectomy or first-generation hormone treatments (LHRH agonists and antagonists, anti-

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androgens) was the only treatment at both CRPC and CSPC until the beginning of our century. This

means that no survival benefit has been gained and no convincing research has been confirmed in

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patients for years. Nevertheless, the last 15 years of research including the first docetaxel studies,

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taxane-specific chemotherapy and new generation hormone therapies have shown life prolongation

in mCRPC and at earlier stages of mCSPC. Abiraterone acetate has been the first new generation
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hormone therapy to be approved in post-chemotherapy mCRPC stage, then in pre-chemotherapy

stage, and finally in mCSPC disease. It has strongly participated in the improvement of metastatic
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prostate cancer prognosis.

When lowering the extracellular level of testosterone by castration becomes insufficient, AA

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demonstrates that the tumor cell is still sensitive to steroid derivates and that the androgen receptor
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still drives important intracellular pathways, guiding tumor growth and progression.
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Oral route treatment may be efficient even after docetaxel failure, and well tolerated. This hormone

therapy has to date a strong impact within a real-world setting and is realistically implemented into
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clinical practice with the inclusion of AA in international guidelines.

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Studies at the mCSPC show that the earlier, the better. In high-risk metastatic prostate cancer, the

early initiation of AA improves overall survival, as well as the time to progression after subsequent

therapy lines. The intensification of hormonal treatment since the diagnosis of metastases will

undoubtedly become the standard of care in upcoming months and beyond. Androgen deprivation

alone will take a step back and become an option only in unfit and older patients with a short life

expectancy.

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 Cancer treatment decision-making is mainly based on survival benefits. Given the large panel of

available life-prolonging agents, future studies should also focus on quality-of-life and patient-

reported outcomes. AA has proven to improve or at least not to alter quality-of-life of patients, even

at early mCSPC when disease-related symptoms are not frequent. Post-approval and phase IV studies

could be clinically relevant to guide treatment choice between two, three, or four new generation

hormone therapies. This choice should also be shared with patient (short-term IV chemotherapy

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versus long-term oral route hormone treatment?) who can be actively involved in treatment

decision-making given the safety profile of each drug and the patient comorbidities.

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Several questions remain open to debate. Is there a place for combination therapy? In other words,

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the stronger, the better? Some studies are ongoing but preliminary findings do not strongly support

this hypothesis for combined new generation hormone treatments.

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The sequential use of new drugs has improved the overall survival of patients with metastatic

prostate cancer. However, few studies, mainly retrospective, have assessed the impact of the order
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of administration.

The ideal sequence at an individual basis remains poorly known. Recent studies have suggested that
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the sequential use of drugs with different mechanisms of action improved the cumulative survival
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and have supported the high risk of cross-resistance between the two new generation hormone
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therapies [46]. The place of AA and other intensification strategies in recurrent, low-volume

metastatic prostate cancer remains debatable. Metastasis-directed therapy by stereotactic body

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radiotherapy or surgery could play a role by postponing the initiation of systemic treatment and
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could challenge intensified combination treatment in that setting.

Last, but not least, the quest for the ideal biomarker, capable to predict prognosis (prognostic

biomarker) or AA treatment response (theranostic biomarker), remains open. Several targets have

been suggested such as AR slice variants or multiple gene signature, none of which are currently used

in routine practice. Research efforts in this field are tremendous. And for that purpose, a simple

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 blood test, able to quantify tumor burden and to characterize mutations spectrum, could be more

efficient than tumor biopsy on primary or metastatic sites.

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 Funding

This paper received no funding.

Declaration of interest

G Ploussard, L Mourey and D Pouessel have received congress invitations, and have served as
consultants and on the advisory board for Janssen. 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

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those disclosed.

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Reviewer disclosures

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A reviewer on this paper has conducted research and/or served as a consultant for; Astellas,
Bayer, Janssen, Pfizer, and Sanofi-Genzyme. Peer reviewers on this manuscript have no other

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relevant financial relationships or otherwise to disclose.

Acknowledgement

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The authors would like to thank Charlotte Somes for English editing of the manuscript.
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 References

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 mCRPC mCSPC
Study COU-AA-301 COU-AA-302 LATITUDE
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Design randomly, double-blind randomly, double-blind randomly, double-blind a

Treatment arm AA + ADT + prednisone AA + ADT + prednisone AA + ADT+ prednisone

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Control arm ADT + prednisone + placebo ADT + prednisone + placebo ADT + dual placebo
Randomization 2:1 1:1 1:1

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Enrollment number 1 195 1088 1 199
Metastatic? 100% 100% 100% de novo

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5% liver
Visceral metastasis 29% 0%

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12% lung
Only High risk patients No No Yes
Previous treatment for
Allowed Allowed No
localized PCa
Prior ADT? Yes
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Previous docetaxel? 100% 0% 0%
PS > 1 10% 0%
Median PSA 128.8 42 23.85
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Follow-up (months) 20.2 49.2 51.8

OS : 0,66 (0,56-0,78)
OS: 0.74 ( 0.64–0.86) 53,3 vs 36,5
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Primary endpoint HR (IC) OS: 0.81 (0.70–0.93)

5.8 vs 11.2 rPFS : 0,47 (0,39-0,55)
Duration (months) 34,7 vs 30,3
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33,0 vs 14,8

Study arm duration treatment

13.8 24 21.8
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median (months)

Table 1: Main Abiraterone Acetate Phase III studies. ADT: Androgen deprivation therapy; CI: confidence interval ;
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mCSPC: metastatic castration-sensitive prostate cancer ;mCRPC: metastatic castration resistant prostate cancer; OS: overall
survival; PCa: prostate cancer; PSA: prostate specific antigen ; rPFS: radiologic progression free survival ; HR: hazard ratio
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Fig 1 : CYP17A1, 17 α-hydro
metaboliism
oxylase/C17,,20 lyase activity
a
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in pregnenolone
p e and prog
gesterone
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Legend: 17 α-hydroxylase
e converts preg
gnenolone and p
progesterone to
o 17-hydroxypre
egnenolone andd 17-hydroxypro
ogesterone.
C17,20 Lyyase convert 17--hydroxypregnenolone to dehyd
droepiandrosterrone.
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Pregnenollone and progessterone can be treated

t to form m
mineralocortico
oids.
17-hydroxyypregnenolone and 17-hydroxy
yprogesterone ccan be treated for
fo the generatio
on of glucocorticcoid such as corrtisol.
17-hydroxyyprogesterone can
c be treated for
f the generatio
on of testosterone.
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Abirateron
ne is an irreversiible 17 α-hydrox
xylase/C17,20 ly
lyase inhibitor and
a decreases glucocorticoid
g annd testosterone
e production
and increa
ases mineraloco
orticoids producttion.
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Informattion Classifica
ation: Genera
al