Enzalutamide treatment of patients with advanced prostate cancer across the disease spectrum: plain language review

ABSTRACT

Goal

To present data from published clinical trials of treatment of patients with prostate cancer with enzalutamide described in plain language and in a dashboard format available at: https://clinical-trials.dimensions.ai/enzalutamide-clinical-review/.

Rationale

Treatments that are clinically active in advanced prostate cancer may benefit patients as they are treated earlier in the disease.

Objective

To show how overall survival improves as patients are treated with enzalutamide earlier in the disease.

1. Introduction

The key terms used throughout this review and their definitions can be seen in the glossary (Table 1).

Table 1.

Glossary: key terms and definitions.

Key term	Definition
Adverse event	An adverse event, or side effect, is a medical event that happens during treatment with a drug or other therapy. Adverse events may be mild, moderate, or severe, and may be caused by something other than the drug or therapy being given.
Castration-resistant prostate cancer (CRPC)	CRPC is a prostate cancer that no longer responds to treatments that lower testosterone. CRPC is also known as hormone‑resistant prostate cancer.
Castration-sensitive prostate cancer (CSPC)	CSPC is a prostate cancer that still responds to treatments that lower testosterone. CSPC is also known as hormone-sensitive prostate cancer.
Biochemically recurrent prostate cancer	Biochemically recurrent prostate cancer is characterized by rising prostate-specific antigen levels following definitive treatment (such as surgery or radiation therapy) and with no metastases (cancer spread) seen on body or bone scans.
Median	If all values are listed in order, the median is the middle value in the list.
Metastasis-free survival (MFS)	MFS is the amount of time from the start of treatment for cancer that a patient is still alive and the cancer has not spread to other parts of the body. In a clinical trial, measuring the MFS is one way to see how well a new treatment works.
Metastatic prostate cancer	Metastatic prostate cancer has spread beyond the prostate to more distant areas of the body.
Overall survival	Overall survival is the amount of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive. In a clinical trial, measuring the overall survival is one way to see how well a new treatment works.
Phase 2 trial	A phase 2 trial tests whether a new treatment works. Phase 2 trials may also provide information about the safety of the new treatment and how the treatment affects the body.
Phase 3 trial	A phase 3 trial tests how well a new treatment works and looks at the safety of the new treatment compared with the current standard treatment. For example, a phase 3 trial may compare which group of patients lives longer and how many side effects patients have. Phase 3 trials usually include more patients than phase 2 trials.
Placebo	A placebo is a substance with no clinical effect and is used as a control in clinical trials.
Primary endpoint	The results for primary endpoints are the most important results in a clinical trial that researchers use to see how well the tested treatment worked.
Prostate cancer	Cancer of the prostate. The prostate is a gland in males that makes semen.
Prostate-specific antigen (PSA)	PSA is a protein made by the prostate gland and found in the blood. A rise in PSA levels can be a sign that the prostate cancer is getting worse.
Progression-free survival (PFS)	PFS is the amount of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. Progression can be measured in different ways, including by body scans. In a clinical trial, measuring the PFS is one way to see how well a new treatment works.
Randomization	In clinical trials, randomization is the process by which participants are assigned to different treatment groups by chance.
Secondary endpoint	The results for secondary endpoints can provide additional information for researchers to see how well a tested treatment worked in a clinical trial.
Skeletal-related (or bone‑related) adverse event	Bone-related events (such as pain) may happen due to treatment or cancer spreading to bone.
Treatment holiday	A break from treatment. Treatment holidays may be used to lower the risk of side effects related to treatment.
Quality of life (QoL)	QoL is the standard of health, comfort, and happiness experienced by an individual or group. QoL can be measured by patient questionnaires.

1.1. What is prostate cancer?

The prostate is part of the male body that helps make semen. It is found between the penis and bladder. Cancer is a disease where abnormal cells multiply and form a tumor. Globally, there were almost 1.5 million new cases of prostate cancer and close to 397,000 deaths related to prostate cancer in 2022. This makes prostate cancer the second most common cancer and fifth highest cause of cancer death in males [1].

1.2. How do prostate cancer treatments work?

Testosterone is a hormone produced by the testicles. It is important for the development and function of male sex organs. Testosterone is also important for the growth and activity of prostate cancer cells [2,3].

Androgen deprivation therapy (ADT) is a treatment used to treat advanced prostate cancer (Table 2). ADT lowers the level of testosterone in the body to stop the prostate cancer from growing. When patients first receive ADT, they may also receive other medicines at the same time as starting ADT. In the past, when patients began receiving ADT, treatment was often combined with first-generation non-steroidal anti-androgens (NSAAs) to treat prostate cancer. More recently, newer, second-generation anti-androgens have been developed. These are also known as androgen receptor pathway inhibitors (ARPIs). Enzalutamide is a type of ARPI used to treat prostate cancer. It has been used to treat 1 million patients across different stages of prostate cancer globally. Enzalutamide works by stopping testosterone from activating androgen receptors. This, in turn, stops or slows the growth of prostate cancer (Figure 1). Other ARPIs include apalutamide, darolutamide, and abiraterone. Abiraterone works differently than the other APRIs by lowering the level of testosterone that the body makes.

Table 2.

Prostate cancer treatments.

Treatment	Description
Androgen deprivation therapy (ADT)	ADT lowers the amount of testosterone that the body makes.
First-generation non‑steroidal anti‑androgen (NSAA)	First-generation NSAAs are older treatments that prevent testosterone from activating cancer cells and causing cancer cells to grow or divide.
Androgen receptor pathway inhibitor (ARPI)	ARPIs are newer treatments that prevent testosterone from activating cancer cells or lower the level of testosterone that the body makes to stop the growth or division of cancer cells.
Chemotherapy	Chemotherapy damages cancer cells that are in the process of dividing into two new cells.

Figure 1.

How enzalutamide works.

1.3. How is prostate cancer classified?

Advanced prostate cancer can be classified in two main ways [4].

One is based on how far it has spread. Prostate cancer begins in the prostate (localized prostate cancer). Once the prostate cancer becomes more advanced, it may spread to other areas close to the prostate. This may include the surrounding lymph nodes or bladder (localized advanced prostate cancer), or more distant areas (metastatic prostate cancer).

The second way of classifying advanced prostate cancer is based on whether the cancer responds to treatments that lower the levels of testosterone (a male sex hormone).

• Castration-sensitive prostate cancer (CSPC), also known as hormone-sensitive prostate cancer (HSPC), still responds to treatments that lower testosterone.

• Castration-resistant prostate cancer (CRPC), also known as hormone-resistant prostate cancer (HRPC), no longer responds to treatments that lower testosterone.

Both CSPC and CRPC can be non-metastatic or metastatic (Figure 2). Patients with non-metastatic prostate cancer may progress to metastatic prostate cancer. Usually, patients progress from metastatic CSPC (mCSPC) to metastatic CRPC (mCRPC).

Figure 2.

Prostate cancer definitions.

^aThere are at least four definitions for castration-sensitive prostate cancer that are used in different guidelines and studies. These include castration-sensitive, castration-naïve, hormone-sensitive, and hormone-naïve prostate cancer.

1.4. What is the focus of this review?

There have been several important studies that have looked at the safety of enzalutamide and how well it works in patients with prostate cancer. The patients included across the studies had different stages of prostate cancer. These included biochemically recurrent prostate cancer, mCSPC, non-metastatic CRPC (nmCRPC), and mCRPC (Table 3). The aim of this review is to look at the results of clinical trials of enzalutamide in patients with different stages of prostate cancer.

Table 3.

Phase 2 and 3 studies with enzalutamide.

Phase 2 studies	Treatments compared	Primary efficacy endpoints
CRPC
STRIVE (NCT01664923)	Enzalutamide versus bicalutamide	PFS
TERRAIN (NCT01288911)	Enzalutamide versus bicalutamide	PFS
Phase 3 studies	Treatments compared	Primary efficacy endpoints	Secondary endpoints
mCRPC
AFFIRM (NCT00974311)	Enzalutamide versus placebo	Overall survival	PSA response, soft tissue response, QoL, time to PSA progression, rPFS, and time to first skeletal-related event
PREVAIL (NCT01212991)	Enzalutamide versus placebo	Overall survival; rPFS	Time to the first skeletal-related event, time to PSA progression, time until patients started chemotherapy, best overall soft tissue response, and a fall in PSA levels of 50% or more from the start of the trial
nmCRPC
PROSPER (NCT02003924)	Enzalutamide versus placebo	MFS	Overall survival, time to PSA progression, time until patients started a new cancer treatment, PSA response rate, and QoL assessments
mCSPC
ARCHES (NCT02677896)	Enzalutamide versus placebo	rPFS	Overall survival, time until patients started a new cancer treatment, time to PSA progression, undetectable PSA rate, objective response rate, and time to deterioration in urinary symptoms
ENZAMET (NCT02446405)	Enzalutamide versus first‑generation NSAA	Overall survival	Clinical PFS and PSA PFS
High-risk biochemically recurrent prostate cancer
EMBARK (NCT02319837)	Enzalutamide and ADT versus placebo and ADT; enzalutamide alone versus placebo and ADT	MFS	MFS for enzalutamide alone compared with ADT alone, time to PSA progression, time until patients started a new cancer treatment, and overall survival

NCT numbers are unique codes that refer to specific studies registered on https://clinicaltrials.gov/.

ADT, androgen deprivation therapy; CRPC, castration-resistant prostate cancer; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; MFS, metastasis-free survival; nmCRPC, non-metastatic castration-resistant prostate cancer; NSAA, non-steroidal anti-androgen; PFS, progression-free survival; PSA, prostate-specific antigen; QoL, quality of life; rPFS, radiographic progression-free survival.

2. Phase 2 trials of enzalutamide in advanced prostate cancer (castration-resistant prostate cancer)

Phase 2 clinical trials test the safety of a new treatment and how well it works as a treatment for a specific disease. The phase 2 STRIVE trial included patients with nmCRPC and mCRPC [5]. The TERRAIN trial included patients with mCRPC only [6]. These trials are important because they looked at the safety of enzalutamide, a type of ARPI, and how well it worked compared with bicalutamide, a first-generation NSAA. The results of STRIVE and TERRAIN led to the later phase 3 trials.

STRIVE and TERRAIN included a similar number of patients within each treatment group [5,6]. Overall, patients who were randomly selected to receive enzalutamide had longer progression-free survival (PFS; see glossary) compared with patients who were randomly selected to receive bicalutamide (Figures 3 and 4) [5,6]. PFS was the primary endpoint, or main outcome (see glossary), that was tested in these trials. In STRIVE, the median PFS was 19 months with enzalutamide and 6 months with bicalutamide [5]. In TERRAIN, the median PFS was 16 months in the enzalutamide group and 6 months in the bicalutamide group [6].

Figure 3.

STRIVE primary endpoint: progression-free survival.

CI, confidence interval; HR, hazard ratio; mg, milligrams; no, number; NR, not reached; PFS, progression-free survival. From Penson DF, Armstrong AJ, Concepcion R, et al. Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate Cancer: The STRIVE Trial, Journal of Clinical Oncology, 34, 18, 2098–2106, https://ascopubs.org/doi/10.1200/JCO.2015.64.9285; © 2016 by American Society of Clinical Oncology.

Figure 4.

TERRAIN primary endpoint: progression-free survival.

CI, confidence interval; HR, hazard ratio. Reprinted from The Lancet Oncology, 17, Shore ND, Chowdhury S, Villers A, et al., Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomized, double-blind, phase 2 study, 153–163, Copyright (2016), with permission from Elsevier.

The number and types of adverse events (or side effects; see glossary) that patients reported with enzalutamide or bicalutamide had some similarities, but there were also differences [5,6]. Side effects can be classified as grade 1, 2, 3, 4, or 5 [7]. Grade 1 side effects are mild and grade 2 side effects are moderate. Grade 3 side effects are severe or medically significant, but not immediately life-threatening, and may require hospitalization. Grade 4 side effects are life-threatening and require urgent medical help. Grades 3 and 4 side effects may result in lowering the treatment dose or stopping treatment. Grade 5 side effects result in death. In both studies, common side effects, which happened in 10% of patients or more, with enzalutamide or bicalutamide included tiredness, back pain, and hot flashes/flushes [5,6]. Some cases of tiredness may have been due to the burden of prostate cancer disease, the effects of low testosterone from ADT treatment, or treatment with enzalutamide or bicalutamide.

Box 1.

Summary.

• Together, the results of STRIVE and TERRAIN suggest that enzalutamide was associated with improved outcomes in patients with nmCRPC and mCRPC compared with bicalutamide.

• This supported the further testing of enzalutamide in phase 3 trials that included more patients.

3. Phase 3 trials of enzalutamide in advanced prostate cancer

In the past section, enzalutamide improved outcomes for patients with prostate cancer compared with bicalutamide. This section covers six international phase 3 trials that looked at the safety of enzalutamide and how well it worked in patients with advanced prostate cancer. Phase 3 trials (see glossary) test the safety of a new treatment and how well it works as a treatment for a specific disease compared with the current standard treatment. The phase 3 AFFIRM, PREVAIL, PROSPER, ARCHES, ENZAMET, and EMBARK trials included patients with different stages of prostate cancer (Figure 2; Table 3): mCRPC, nmCRPC, mCSPC, and high-risk biochemical recurrence, respectively. Overall survival (see glossary) has been the “gold standard” endpoint for regulatory agencies to approve medicines for the treatment of diseases. The approval and expanded approvals for enzalutamide to treat the different stages of advanced prostate cancer were based on data from these trials. In these trials, patients received:

• ADT with enzalutamide or ADT with placebo (see glossary; AFFIRM, PREVAIL, PROSPER, and ARCHES)

• ADT with enzalutamide or ADT with first-generation NSAA (ENZAMET)

• ADT with enzalutamide, ADT with placebo, or enzalutamide alone (EMBARK).

Data from the phase 3 trials discussed in this review are presented in a dashboard available at: https://clinical-trials.dimensions.ai/enzalutamide-clinical-review/.

4. Phase 3 trials in metastatic castration-resistant prostate cancer: AFFIRM and PREVAIL

4.1. Trial design and patients

AFFIRM and PREVAIL both included patients with mCRPC, although only the patients in AFFIRM received chemotherapy (Table 2) before entering the trial [8,9]. In both trials, patients received ADT with enzalutamide or ADT with placebo. Patient characteristics were generally well balanced between treatment groups [8,9].

4.2. Overall survival and radiographic progression-free survival

AFFIRM and PREVAIL both had overall survival as their primary endpoint. To measure overall survival, patients with mCRPC were studied for a median of 14 months for AFFIRM and 22 months for PREVAIL [8,9]. Enzalutamide lowered the chance of death compared with placebo by 37% in AFFIRM and 29% in PREVAIL [8,9]. The median overall survival in patients with mCRPC who were randomly selected to receive enzalutamide was longer in PREVAIL (32 months) than AFFIRM (18 months) [8,9]. This improvement may be partly because patients in PREVAIL had not received chemotherapy before study treatment. PREVAIL also had a second primary endpoint of radiographic progression-free survival (rPFS; see glossary). rPFS was a secondary endpoint (see glossary) in AFFIRM. The median rPFS was 8 months in AFFIRM and not reached in PREVAIL [8,9].

4.3. Secondary endpoints

Enzalutamide showed improved outcomes for all secondary endpoints in AFFIRM and PREVAIL compared with placebo [8,9]. The time to the first skeletal-related event (or bone-related event; see glossary) was longer for patients with mCRPC who received enzalutamide compared with placebo in AFFIRM (17 months versus 13 months) but similar in PREVAIL (31 months for each group) [8,9]. The time until a rise in prostate-specific antigen (PSA; see glossary) levels was also longer in patients with mCRPC who received enzalutamide compared with placebo in AFFIRM (8 months versus 3 months) and PREVAIL (11 months versus 3 months) [8,9].

4.4. Safety

The rate of side effects leading to death was low but similar between the enzalutamide group (3%, 23 out of 800 patients) and placebo group (4%, 14 out of 399 patients) in AFFIRM and in PREVAIL (enzalutamide group: 4%, 37 out of 871 patients; placebo group: 4%, 32 out of 844 patients) [8,9]. In both studies, the amount and type of side effects in patients with mCRPC who received enzalutamide compared with placebo had similarities, but there were also differences (Table 4) [8,9]. Tiredness (of any grade), diarrhea, and hot flashes/flushes were common in both studies (less common for grade 3 or 4 side effects) [8,9]. In both studies, tiredness and hot flashes/flushes were more common with enzalutamide compared with placebo [8,9].

Table 4.

Common side effects in phase 3 trials of enzalutamide.

All-grade adverse events, %	AFFIRM (mCRPC)		PREVAIL (mCRPC)		PROSPER (nmCRPC)		ARCHES (mCSPC)		ENZAMET (mCSPC)		EMBARK (high-risk biochemically recurrent prostate cancer)
	Enzalutamide	Placebo	Enzalutamide	Placebo	Enzalutamide	Placebo	Enzalutamide	Placebo	Enzalutamide	First-generation NSAA	Enzalutamide	Enzalutamide alonea	Placebo
Hot flashes/flushes	20	10	18	8	13	8	27	22	68	62	69	22	57
Tiredness	34	29	52	35	46	22	20	15	83	65	43	47	33
Joint pain	–	–	–	–	–	–	12	11	15	13	27	23	21
Back pain	–	–	–	–	–	–	8	11	30	27	17	18	15
Increased weight	–	–	–	–	–	–	6	8	6	7	–	–	–
High blood pressure	–	–	18	5	18	6	9	6	21	13	23	19	19
Diarrhea/select gastro-intestinal events	21	18	49	42	10	10	6	6	20	18	14	13	9
Edema (angio- or peripheral)b	–	–	11	8	2	1	5	7	19	18	8	9	10
Nausea	–	–	–	–	11	9	7	5	24	15	12	15	8
Physical weakness	–	–	13	8	-	-	5	5	–	–	11	11	6
Constipation	–	–	22	17	9	7	5	5	23	19	13	10	9
Musculo-skeletal pain/eventc	14	10	47	37	34	23	6	4	–	–	–	–	–
Headache	12	6	10	7	9	5	–	–	13	9	11	12	9
Dizziness	–	–	–	–	10	4	5	4	14	7	11	12	10

Percentages are rounded to the nearest whole number.

^aAll of the patients in the treatment groups across the phase 3 trials received ADT as part of their treatment, except for the enzalutamide alone group in EMBARK, in which patients received only enzalutamide.

^bSwelling under the skin and hands or lower legs due to the buildup of fluid.

^cPain or an event related to the muscle or bone.

ADT, androgen deprivation therapy; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; nmCRPC, non-metastatic castration-resistant prostate cancer; NSAA, non-steroidal anti-androgen.

4.5. Quality of life

In addition to improving survival and slowing the growth or spread of cancer, maintaining a good quality of life (QoL; see glossary) is a very important goal for patients and physicians. In AFFIRM and PREVAIL, questionnaires were used to measure QoL [10,11]. A separate review of important enzalutamide trials, including AFFIRM and PREVAIL, studied QoL with enzalutamide treatment in more detail [12]. In both studies, enzalutamide was associated with benefits in QoL, which worsened more slowly with enzalutamide compared with placebo [10,11]. In AFFIRM, more patients with mCRPC who received enzalutamide had improvements in questionnaire scores compared with patients who received placebo (43% versus 18%) [10]. These results show that enzalutamide had clinically beneficial effects on QoL compared with placebo in patients with mCRPC.

Box 2.

Summary.

• In patients with mCRPC, enzalutamide was associated with longer overall survival, improved outcomes for all secondary endpoints, and clinically beneficial effects on QoL compared with placebo.

• Median overall survival improved following treatment with enzalutamide for patients with mCRPC (18 months for AFFIRM and 32 months for PREVAIL).

• Enzalutamide had a tolerable safety profile in patients with mCRPC. Common side effects included tiredness, diarrhea, and hot flashes/flushes.

5. Phase 3 trial in non-metastatic castration-resistant prostate cancer: PROSPER

5.1. Trial design and patients

PROSPER included patients with nmCRPC [13]. The patients in PROSPER were like those in AFFIRM and PREVAIL in that their cancer was castration-resistant, but different in that their cancer was not metastatic (had not spread). Researchers used body or bone scans to tell if the cancer had spread. In PROSPER, patients with nmCRPC received ADT with enzalutamide or ADT with placebo. Patient characteristics were generally well balanced between treatment groups [13,14].

5.2. Metastasis-free survival

PROSPER had a primary endpoint of metastasis-free survival (MFS; see glossary). Slowing the spread of cancer and the related effects on patient QoL is very important to patients and doctors. To measure MFS, patients with nmCRPC in PROSPER were studied for a median of 19 months (enzalutamide group) and 15 months (placebo group) [13]. Median MFS was 37 months in the enzalutamide group and 15 months in the placebo group (Figure 5) [13]. This suggests that enzalutamide slowed the spread of cancer by around 2 years in PROSPER.

Figure 5.

PROSPER primary endpoint: metastasis-free survival.

CI, confidence interval; mo, months; no, number; NR, not reached. From New England Journal of Medicine, Hussain M, Fizazi K, Saad F, et al., Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer, 378, 2465–2474. Copyright © (2018) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

5.3. Secondary endpoints

Enzalutamide lowered the chance of death by 27% in PROSPER compared with placebo [15]. This is similar to what was found for mCRPC patients in AFFIRM and PREVAIL [8,9]. Median overall survival for patients who were randomly selected to receive enzalutamide was 67 months in the final overall survival analysis (median follow-up: 48 months) [13,15]. This was longer than in mCRPC patients. These results suggest that patients with nmCRPC who received enzalutamide lived longer than those with mCRPC. This supports the idea that patients with earlier-stage disease live longer than patients with later-stage disease. However, it is important to note that the time that patients were studied for to measure overall survival was different between the trials. The median follow-up time for the earlier-stage trials was longer than the later-stage trials (AFFIRM, 14 months; PREVAIL, 22 months; PROSPER, 48 months) [8,9,15].

The time until a rise in PSA levels was longer in patients who received enzalutamide compared with placebo (37 months versus 4 months) [13]. This shows an improvement from patients with mCRPC (AFFIRM, 8 months; PREVAIL, 11 months) to patients with nmCRPC (PROSPER, 37 months). These results further suggest that patients with earlier-stage disease (nmCRPC) have improved outcomes compared with patients with later-stage disease (mCRPC) [8,9,13]. This is a similar finding to the improvement in overall survival seen from mCRPC to nmCRPC. The time until patients started a new cancer treatment was also improved in patients who received enzalutamide compared with placebo in PROSPER (40 months versus 18 months) [13]. Patients may need to start a new treatment if their disease worsens.

5.4. Safety

The number of patients who died while receiving enzalutamide (3%, 32 out of 930 patients) was slightly higher compared with patients who received placebo (1%, 3 out of 465 patients). Whereas, in patients with mCRPC (AFFIRM and PREVAIL), the deaths related to side effects were more similar between the treatment groups [8,9,13]. In PROSPER, side effects happened more often with enzalutamide treatment compared with placebo. Tiredness, hot flashes/flushes, and diarrhea were common side effects with enzalutamide treatment [13]. These side effects were similar to patients with mCRPC (AFFIRM and PREVAIL) who received enzalutamide (Table 4) [8,9].

5.5. Quality of life

In PROSPER, enzalutamide showed a clinical benefit by delaying the progression of pain, the worsening of symptoms, and a decrease in functional status, compared with placebo [16]. This suggests that enzalutamide may help to maintain QoL in patients with nmCRPC, a similar finding to patients with mCRPC from AFFIRM and PREVAIL.

Box 3.

Summary.

• Following treatment with enzalutamide, the median overall survival in patients with nmCRPC (67 months) improved compared with patients who had mCRPC (AFFIRM, 18 months; PREVAIL, 32 months).

• The time until a rise in PSA levels also improved in patients with mCRPC (AFFIRM, 8 months; PREVAIL, 11 months) to patients with nmCRPC (PROSPER, 37 months).

• In PROSPER, enzalutamide had a tolerable safety profile, with relatively uncommon grades 3 and 4 side effects, and may help to maintain QoL. Like AFFIRM and PREVAIL, common side effects included tiredness, hot flashes/flushes, and diarrhea.

• The results of PROSPER support enzalutamide as a clinically active treatment for advanced prostate cancer. These results support the idea that patients with earlier-stage disease have improved outcomes compared with patients with later-stage disease.

6. Phase 3 trials in metastatic castration-sensitive prostate cancer: ARCHES and ENZAMET

6.1. Trial design and patients

ARCHES and ENZAMET included patients with mCSPC. In these trials, past treatment with chemotherapy was allowed [17,18]. The patients in ARCHES and ENZAMET were different from patients in AFFIRM, PREVAIL, and PROSPER, in that their cancer was castration-sensitive and not castration-resistant. In ARCHES, patients received ADT with enzalutamide or ADT with placebo. In ENZAMET, patients received ADT with enzalutamide or ADT with first-generation NSAA. Some patients in ENZAMET also received docetaxel. Patient characteristics were generally well balanced between treatment groups [17].

6.2. Overall survival and radiographic progression-free survival

ENZAMET had overall survival as a primary endpoint. Overall survival was a secondary endpoint in ARCHES. In patients with mCSPC, enzalutamide lowered the chance of death by 34% in ARCHES compared with placebo and 30% in ENZAMET when compared with first-generation NSAA [19,20]. This is similar to the findings in patients with mCRPC (AFFIRM and PREVAIL) and nmCRPC (PROSPER) [8,9,15]. Median overall survival was not reached in the patients who were randomly selected to receive enzalutamide for both studies, including in the updated or final analyses (median follow‑up: ENZAMET, 68 months; ARCHES, 45 months) [17–20].

Across advanced prostate cancer disease stages from mCRPC to mCSPC, enzalutamide lowered the chance of death by around 30% (ranging from 27% to 37%) compared with the placebo or first-generation NSAA groups [8,9,15,19,20]. This highlights that enzalutamide works as a treatment in advanced prostate cancer and was associated with a lower chance of death across different stages of the disease from mCRPC (AFFIRM: 37%; PREVAIL: 29%), to nmCRPC (PROSPER: 27%), to mCSPC (ARCHES: 34%; ENZAMET: 30%) [8,9,15,19,20].

The primary endpoint of ARCHES was rPFS, which was a secondary endpoint in ENZAMET. The median rPFS for patients who received enzalutamide in ARCHES was 50 months and 81 months for ENZAMET [19,20]. This is an increase from patients with mCRPC (AFFIRM, 8 months) and suggests that rPFS with enzalutamide was improved in patients with mCSPC compared with mCRPC [8]. This is a similar finding to the results for overall survival and time to PSA progression.

6.3. Secondary endpoints

The time until patients started a new cancer treatment was improved in patients who received enzalutamide compared with placebo in ARCHES (30 months versus not reached) [17]. This is supported by a similar finding in patients who received enzalutamide in nmCRPC (PROSPER, 40 months) [13], but did not improve from nmCRPC to mCSPC. The median time until a rise in PSA levels was improved in patients who received enzalutamide in ENZAMET compared with first-generation NSAA (68 months versus 22 months) [20].

6.4. Safety

In ARCHES, side effects leading to death were similar between patients who received enzalutamide (2%, 14 out of 572 patients) and placebo (2%, 10 out of 574 patients) [17]. Similar to patients with mCRPC and nmCRPC, tiredness with enzalutamide treatment was common in patients with mCSPC (Table 4) [17,18]. In patients treated with enzalutamide, tiredness was more common in ENZAMET (83%, 465 out of 563 patients) than in ARCHES (20%, 112 out of 572 patients) [17,18].

6.5. Quality of life

In ARCHES, researchers measured QoL using a questionnaire [21]. There was no difference between enzalutamide and placebo in the time to worsening of worst pain and pain severity. This suggests that enzalutamide does not worsen health-related QoL [21]. In ENZAMET, enzalutamide was associated with worse self-ratings of tiredness, physical function, and cognitive function, but not overall health and QoL [22]. The negative effects on tiredness, physical function, and cognitive function were seen in ENZAMET, but not ARCHES [21,22]. Overall, these results suggest that treatment with enzalutamide may help to maintain QoL in patients with mCSPC, who generally have good QoL before treatment.

Box 4.

Summary.

• Enzalutamide lowered the chance of death in patients with mCSPC (ARCHES: 34%; ENZAMET: 30%) by a similar amount compared with patients who had nmCRPC (PROSPER: 27%) and mCRPC (AFFIRM: 37%; PREVAIL: 29%).

• The rPFS of patients treated with enzalutamide increased in mCSPC (ARCHES: 50 months; ENZAMET: 81 months) from mCRPC (AFFIRM: 8 months).

• Enzalutamide had a tolerable safety profile in patients with mCSPC and may help to maintain QoL. Tiredness was common in mCSPC, similar to patients treated with enzalutamide in studies of patients with nmCRPC and mCRPC.

• The results of enzalutamide treatment in patients with mCSPC highlight that enzalutamide works as a treatment in advanced prostate cancer across different stages of the disease and supports the use of enzalutamide earlier in the disease.

7. Phase 3 trial in high-risk biochemically recurrent prostate cancer: EMBARK

7.1. Trial design and patients

The phase 3 EMBARK trial included patients who had non-metastatic CSPC with high-risk biochemically recurrent prostate cancer [23]. Patients in EMBARK had rising PSA levels after past treatment such as surgery or radiation therapy. Rising PSA levels can be a sign that the prostate cancer has come back after treatment or that the cancer is worsening. EMBARK is the first trial that looked at the safety of enzalutamide and how well it worked in patients in this earlier stage of the disease. Patients in EMBARK were divided into three groups and received either ADT with enzalutamide, ADT with placebo (ADT alone), or enzalutamide alone. The results for enzalutamide with ADT and enzalutamide alone were compared with ADT alone. If a patient’s PSA level was low after 9 months of treatment, the patient took a treatment holiday (see glossary). Patients restarted treatment if their PSA levels went above a certain amount. Patient characteristics were generally well balanced between treatment groups [23].

7.2. Metastasis-free survival

EMBARK had a primary endpoint of MFS for the ADT with enzalutamide group compared with the ADT alone group. To measure MFS, patients with high-risk biochemically recurrent prostate cancer in EMBARK were studied for a median of 61 months [23]. Overall, patients who received ADT with enzalutamide or enzalutamide alone had improved MFS compared with patients who received ADT alone [23].

7.3. Secondary endpoints

The time until a rise in PSA levels was improved for both enzalutamide treatment groups compared with ADT alone [23]. The time until patients received a new cancer treatment was also improved for both enzalutamide treatment groups compared with ADT alone. A longer patient follow-up is needed to properly measure overall survival.

7.4. Safety

In EMBARK, side effects leading to death were similar between patients who received ADT with enzalutamide (2%, 6 out of 353 patients) and enzalutamide alone (2%, 8 out of 354 patients) compared with ADT alone (1%, 3 out of 354 patients). No new side effects were found with enzalutamide treatment in EMBARK beyond what had been seen in earlier enzalutamide trials [23]. For all treatment groups, tiredness and hot flashes/flushes were common side effects [23]. Gynecomastia (enlargement of the breast in males) was also common in the enzalutamide alone group [23].

7.5. Quality of life

The median time that it took until QoL worsened was similar between patients who received ADT with enzalutamide or enzalutamide alone compared with ADT alone [24]. Overall, these results suggest that treatment with enzalutamide may help to maintain QoL in patients with high-risk biochemical recurrence.

Box 5.

Summary.

• Enzalutamide improved outcomes in patients with high-risk biochemically recurrent prostate cancer.

• Based on the results of EMBARK, the US Food and Drug Administration approved enzalutamide with or without ADT (including leuprolide) for the treatment of non-metastatic CSPC with biochemical recurrence at high-risk for metastasis.

• These results further support the use of enzalutamide as a treatment with a tolerable safety profile in the earlier stages of the disease, including high-risk biochemically recurrent prostate cancer.

8. Concluding statements

The phase 2 trials of enzalutamide in patients with CRPC (STRIVE and TERRAIN) showed that enzalutamide improved PFS compared with bicalutamide. This led to the further study of enzalutamide in larger phase 3 trials. Across the phase 3 trials, patient characteristics were generally well balanced between treatment groups.

The phase 3 trials of enzalutamide in patients with advanced prostate cancer showed that patients with earlier-stage disease had improved outcomes compared with patients who had later-stage disease. Overall survival and other outcomes improved from mCRPC (AFFIRM and PREVAIL), to nmCRPC (PROSPER), to mCSPC (ARCHES and ENZAMET) (Figure 6). There was also improvement in MFS and other outcomes in patients with high-risk biochemically recurrent prostate cancer who received enzalutamide alone or with ADT.

Box 6.

Summary.

• In six large, global, randomized phase 3 trials, enzalutamide improved clinical outcomes including overall survival in patients with different stages of advanced prostate cancer.

• Overall, enzalutamide had a tolerable safety profile across the studies.

• Overall QoL was maintained with enzalutamide treatment at different stages of advanced prostate cancer.

• We look forward to the results of studies of enzalutamide in earlier stages of prostate cancer. These include the results of ENZARAD, an ongoing trial in patients with localized prostate cancer.

Figure 6.

Summary of key points.

In AFFIRM, PREVAIL, PROSPER, and ARCHES, patients received either enzalutamide or placebo. In ENZAMET, patients received either enzalutamide or first-generation non-steroidal anti-androgens.LPC, locally advanced prostate cancer; mCRPC, metastatic castration-resistant prostate cancer; mCSPC, metastatic castration-sensitive prostate cancer; nmCRPC, non-metastatic castration-resistant prostate cancer; nmCSPC, non-metastatic castration-sensitive prostate cancer; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival.

Overall, enzalutamide had a tolerable safety profile in patients with mCRPC, nmCRPC, mCSPC, and high-risk biochemically recurrent prostate cancer. Tiredness, hot flashes/flushes, and diarrhea were common side effects with enzalutamide treatment across the phase 3 trials. Overall QoL was maintained with enzalutamide treatment at different stages of advanced prostate cancer.

At present, enzalutamide is the only ARPI that has demonstrated clinical activity in all advanced prostate cancer settings (mCRPC, nmCRPC, mCSPC, and high-risk biochemical recurrence). Treatments that work in advanced prostate cancer may be of benefit to patients earlier in the disease.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Funding Statement

This paper was sponsored by Astellas Pharma and Pfizer Inc.

Disclosure statement

Paul E. Dato – consulting or advisory role: Bayer, Dendreon, Pfizer Inc., Astellas Pharma, Johnson & Johnson Innovative Medicine (formerly Janssen), and Sumitomo Pharma America Inc. (formerly Myovant Sciences Inc.); research funding: CLS Laser, Ortho Clinical Diagnostics, Bayer, Convergent Genomics, Exosome Diagnostics, LabCorp, Neuspera, OncoCellMDx, Ortho Clinical Diagnostics, Urogen, and Veracity.

Jose De La Cerda – consulting or advisory role: Dendreon, Pfizer Inc., Astellas Pharma, and Johnson & Johnson Innovative Medicine (formerly Janssen).

Andrew J. Armstrong – consulting or advisory role: Bayer, Dendreon, Pfizer Inc., Astellas Scientific and Medical Affairs Inc., AstraZeneca, Merck, Bristol Myers Squibb, Johnson & Johnson Innovative Medicine (formerly Janssen), FORMA Therapeutics, Novartis, Exelixis, Sumitomo Pharma America Inc. (formerly Myovant Sciences Inc.), and GoodRx; institutional research funding: Dendreon, Bayer, Pfizer Inc., Novartis, Johnson & Johnson Innovative Medicine (formerly Janssen), Astellas Pharma, Gilead Sciences, Roche/Genentech, Bristol Myers Squibb, Constellation Pharmaceuticals, Merck, AstraZeneca, BeiGene, Amgen, and FORMA Therapeutics; patents, royalties, other intellectual property: circulating tumor cell novel capture technology (institution); travel, accomodation, and expenses: Astellas Scientific and Medical Affairs Inc.

Arun A. Azad – honoraria: Johnson & Johnson Innovative Medicine (formerly Janssen), Astellas Pharma, Novartis, Tolmar, Amgen, Pfizer Inc., Bayer, Telix Pharmaceuticals, Bristol Myers Squibb, Merck Serono, AstraZeneca, Sanofi, Ipsen, Merck Sharp & Dohme, Noxopharm, Aculeus Therapeutics, and Daiichi Sankyo; consulting or advisory role: Astellas Pharma, Novartis, Johnson & Johnson Innovative Medicine (formerly Janssen), Sanofi, AstraZeneca, Pfizer Inc., Bristol Myers Squibb, Tolmar, Telix Pharmaceuticals, Merck Sharp & Dohme, Bayer, Ipsen, Merck Serono, Amgen, Noxopharm, Aculeus Therapeutics, Daiichi Sankyo, and Arvinas; speaker’s bureau: Astellas Pharma, Novartis, Amgen, Bayer, Johnson & Johnson Innovative Medicine (formerly Janssen), Ipsen, Bristol Myers Squibb, and Merck Serono; research funding: Astellas Pharma, AstraZeneca, Merck Serono, Merck Serono (to institution), Novartis (to institution), Pfizer Inc. (to institution), Bristol Myers Squibb (to institution), Sanofi (to institution), AstraZeneca (to institution), GlaxoSmithKline (to institution), Aptevo Therapeutics (to institution), MedImmune (to institution), Bionomics (to institution), Synthorx (to institution), Astellas Pharma (to institution), Ipsen (to institution), Lilly (to institution), Gilead Sciences (to institution), Johnson & Johnson Innovative Medicine (to institution; formerly Janssen), Exelixis (to institution), and Merck Sharpe & Dohme to institution); travel, accomodation, and expenses: Astellas Pharma, Sanofi, Merck Serono, Amgen, Johnson & Johnson Innovative Medicine (formerly Janssen), Tolmar, and Pfizer Inc.

Ciara Conduit – honoraria: AstraZeneca.

Gabriel P. Haas – employment and shareholder: Astellas Pharma, Inc.

Kenneth Kernen – consultant: Astellas Pharma, Bayer, Johnson & Johnson Innovative Medicine (formerly Janssen), Merck Sharpe & Dohme, Olympus Corporation of the Americas, and Pfizer Inc.

Zachary W. Klaassen – honoraria: Astellas Pharma, Bayer, and Pfizer Inc.; consulting or advisory role: Sesen Bio.

Raj Patel – employment: Bristol Myers Squibb; was employed by Pfizer Inc. at the time of manuscript development.

Fred Saad – consultant: Astellas Pharma, Johnson & Johnson Innovative Medicine (formerly Janssen), Sanofi, and AstraZeneca/MedImmune; speaker’s bureau: Astellas Pharma, Johnson & Johnson Innovative Medicine (formerly Janssen), Sanofi, Bayer, and AstraZeneca; institutional funding: Astellas Pharma, Bayer, Johnson & Johnson Innovative Medicine (formerly Janssen), Sanofi, and AstraZeneca.

Neal D. Shore – consultant and grant support: AbbVie, Amgen, Astellas Pharma, Bayer, Dendreon Pharmaceuticals, Ferring Pharmaceuticals, Johnson & Johnson Innovative Medicine (formerly Janssen), Pfizer Inc., Sanofi, Genzyme, and Tolmar Pharmaceuticals.

Stephen J. Freedland – consultant: Astellas Pharma, AstraZeneca, Bayer, Eli Lilly, Johnson & Johnson Innovative Medicine (formerly Janssen), Merck, Novartis, Pfizer Inc., Sanofi, and Sumitomo Pharma America Inc. (formerly Myovant Sciences Inc.).

Lawrence I. Karsh – consultant: Astellas Pharma, AstraZeneca, AbbVie, Bayer, Bristol Myers Squibb, Dendreon, Ferring, Johnson & Johnson Innovative Medicine (formerly Janssen), Merck, Sumitomo Pharma America Inc. (formerly Myovant Sciences Inc.), Pfizer Inc., and Sanofi; clinical trials: AbbVie, AdventHealth Urology (formerly the Urology Center of Colorado), Astellas Pharma, AstraZeneca, Bayer, Bioxcel, Bristol Myers Squibb, Dendreon, Epizyme, Ferring, Johnson & Johnson Innovative Medicine (formerly Janssen), Merck, Sumitomo Pharma America Inc. (formerly Myovant Sciences Inc.), and Pfizer Inc.; speaker’s bureau: Astellas Pharma, AstraZeneca, Bayer, Dendreon, Johnson & Johnson Innovative Medicine (formerly Janssen), Lantheus, Merck, Sumitomo Pharma America Inc. (formerly Myovant Sciences Inc.), and Pfizer Inc.

Writing disclosure

Medical writing and editorial support were provided by Adam Anazim, BSc, Julie B. Stimmel, PhD, CMPP, and Rosie Henderson, MSc, of Onyx (a division of Prime, London, UK), funded by Pfizer Inc. and Astellas Pharma Inc., the co-developers of enzalutamide. The authors were involved in the collection and interpretation of information provided in the manuscript, and ultimate responsibility for opinions and conclusions lies with the authors.

Dashboard development support was provided by Erikka Brewer, Aleksandr Ihnatsiuk, and Rachel Floyd at Digital Science (London, UK), and dashboard editorial support was provided by Adam Anazim, BSc, Julie B. Stimmel, PhD, CMPP, and Rosie Henderson, MSc, of Onyx (a division of Prime, London, UK), funded by Pfizer Inc. and Astellas Pharma Inc. The dashboard includes previously unpublished data on patient-reported outcomes from the PROSPER (NCT02003924) and ARCHES (NCT02677896) studies, which were sponsored by Pfizer Inc. and Astellas Pharma Inc.

Author contributions

Paul E. Dato – conceptualization, methodology, investigation, writing – original draft preparation, review, and editing, project administration, and supervision.

Jose De La Cerda – conceptualization, methodology, investigation, and writing – original draft preparation, review, and editing.

Andrew J. Armstrong – conceptualization, methodology, investigation, and writing – original draft preparation, review, and editing.

Arun A. Azad – conceptualization, methodology, investigation, and writing – original draft preparation, review, and editing.

Ciara Conduit – conceptualization, methodology, investigation, and writing – original draft preparation, review, and editing.

Gabriel P. Haas – conceptualization, methodology, investigation, writing – original draft preparation, review, and editing, and funding acquisition.

Kenneth Kernen – conceptualization, methodology, investigation, and writing – original draft preparation, review, and editing.

Zachary W. Klaassen – conceptualization, methodology, investigation, and writing – original draft preparation, review, and editing.

Raj Patel – conceptualization, methodology, investigation, writing – original draft preparation, review, and editing, project administration, and funding acquisition.

Fred Saad – conceptualization, methodology, investigation, and writing – original draft preparation, review, and editing.

Neal D. Shore – conceptualization, methodology, investigation, and writing – original draft preparation, review, and editing.

Stephen J. Freedland – conceptualization, methodology, investigation, and writing – original draft preparation, review, and editing.

Lawrence I. Karsh – conceptualization, methodology, investigation, writing – original draft preparation, review, and editing, project administration, and supervision.

All authors read and approved the final manuscript.

Data availability statement

PROSPER: Upon request and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

ARCHES: Researchers may request access to anonymized participant-level data, trial-level data, and protocols from Astellas-sponsored clinical trials at www.clinicalstudydatarequest.com. For the Astellas criteria on data sharing, see https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx.

Ethical conduct of research

The trials included in this review were conducted according to the provisions of the Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonisation. All patients provided written informed consent to participate in these trials.