Hormone Therapy for Castration-Resistant Prostate Cancer: Comparison
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Prostate cancer (PCa) is the most common cancer and the second deadliest cancer among men in the United States, which is mainly due to metastatic disease. In general, surgery or radiation is potentially a curative treatment for localized disease. Since PCa is characterized as a typical androgen-dependent disease, hormone therapy (i.e., androgen deprivation therapy (ADT)) is the most effective therapy to control metastatic disease. However, almost all patients eventually develop castration-resistant PCa (CRPC) within 12 to 18 months, with a median survival of 14 to 26 months. Nowadays, new anti-androgens (Enzalutamide or Abiraterone), radiotherapy (Radium-223) or immunotherapy (sipuleucel-T) have been approved for metastatic CRPC (mCRPC) patients to prolong the overall survival. Inevitably, mCRPC further acquires resistance and becomes therapy- and castration-resistant PCa (t-CRPC), which is considered as an end-stage disease without effective therapy, and on which new therapeutic strategies have been actively explored.

  • castration-resistant prostate cancer
  • recurrent therapy and castration-resistant prostate cancer
  • precision medicine

1. Enzalutamide

In Prostate cancer (PCa), androgen receptor (AR) activated by androgens still represents a critical oncogenic pathway. Enzalutamide is a novel antiandrogen agent that can block AR with high affinity compared to traditional antiandrogens such as bicalutamide or flutamide [1]. Besides direct binding to AR, it can reduce AR translocation into the nucleus and prevent its transcription by binding to DNA [2] (Figure 1).
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Figure 1. Molecular mechanism of the therapies for prostate cancer.
Enzalutamide was approved by the Food and Drug Administration (FDA) in 2012 for use on metastatic castration-resistant PCa (CRPC)RPC based on the randomized, phase III trial study (AFFIRM) [3][4] (Table 1). The study demonstrated that patients who received enzalutamide after chemotherapy improved median survival from 13.6 to 18.4 months (HR: 0.63 p < 0.001). Another phase III, double-blind, randomized study (PREVAIL) (Table 1) compared patients receiving enzalutamide before chemotherapy and showed that radiographic progression-free survival (rPFS) and overall survival (OS) benefit from 31.3 to 35.3 months [5][6]. It also can delay the initiation of chemotherapy in patients with metastatic PCa. In the phase III randomized trial (PROSPER), enzalutamide demonstrated the benefit of metastasis-free survival rate compared to placebo (36.6 months vs. 14.7 months, p < 0.001) in patients with non-metastatic CRPC (nmCRPC) [7] (Table 1). Therefore, the FDA expand the use of enzalutamide in patients with nmCRPC since 2018.
Table 1.
FDA-approved therapies for prostate cancer.
Drug Class Therapy Indication Clinical

Trial		 Efficacy

(Mon.)		 Impact on PCa Treatment Reference
2nd-generation antiandrogen Enzalutamide mCRPC AFFIRM OS 18.4 vs. 13.6 ENZ improves OS

after chemotherapy		 [4]
PREVAIL OS 35.3 vs. 31.3 ENZ improves OS in

chemotherapy naïve		 [5][6]
nmCRPC PROSPER MFS 36.6 vs. 14.7 ENZ decreases the risk of metastasis [7]
mCSPC ENZEMET 80% vs. 72%

(3-year OS)		 ENZ improves OS and decreases disease progression [8]
ARCHES rPFS

NR vs. 19.0		 ENZ decreases the risk of metastatic progression [9]
Apalutamide nmCRPC SPARTAN MFS 40.5 vs. 16.2 APA decreasse the risk of metastasis [10]
mCSPC TITAN 2-year OS

82.4 vs. 73.5		 APA improves OS and PFS [11]
Darolutamide nmCRPC ARAMIS MFS 40.4 vs. 18.4 DA decreases the risk of metastasis [12]
Abiraterone mCRPC COA-301 OS 15.8 vs. 11.2 AB improves OS

after chemotherapy		 [13]
COA-302 OS 34.7 vs. 30.3 AB improves OS in

chemotherapy naïve		 [14]
High-volume CSPC LATITUDE OS 53.3 vs. 36.5 AB improves OS in

high-risk CSPC		 [15][16]
Radiotherapy Radium 223 CRPC with symptomatic bone metastasis, no visceral metastasis ALSYMPCA OS 14.9 vs. 11.3 RA-223 improves OS in symptomatic bony metastatic mCRPC [17]
177Lu-PSMA 617 PSMA-positive mCRPC and already treated with ARB and chemotherapy VISION OS 15.3 vs. 11.3

rPFS 8.7 vs. 3.4		 177Lu-PSMA 617 improves OS and rPFS in PSMA-positive mCRPC [18]
Immunotherapy Sipuleucel-T mCRPC IMPACT OS 25.8 vs. 21.7 Sipuleucel-T improves OS in mCRPC [19]
PARP-I Olaparib mCRPC with HRR genes mutation after ENZ or AB PROfound OS 18.5 vs.15.1

rPFS 7.4 vs. 3.6		 Olaparib improves OS and rPFS in mCRPC with HRR gene mutation [20]
Rubraca mCRPC with BRCA genes after ARB or chemotherapy TRITON2

(phase2)

TRITON3

(phase3)		 ORR 43.5% (IRR)

PSA response rate 54.8%		 Rubraca has the antitumor activity in mCRPC with BRCA gene mutation [21][22]
PCa = prostate cancer; nmCRPC = non-metastatic castration-resistant prostate cancer; mCSPC = metastatic castration-sensitive prostate cancer; mCRPC = metastatic castration-resistant prostate cancer; OS = overall survival; rPFS = Radiographic progression-free survival; FDA = Food and Drug Administration; ENZ = Enzalutamide; APA = Apalutamide; DA = Darolutamide; AB = Abiraterone; MFS = metastatic-free survival; NR = non-reached; RA-223 = Radium 223; ARB = androgen receptor blocker; HRR = homologous recombination repair; ORR = objective response rate; IRR = independent radiology review; PARP-I = Polyadenosine diphosphate ribose polymerase inhibitors.
In patients with metastatic, hormone-sensitive PCa (mHSPC), enzalutamide improved the overall survival rate and progression-free survival over standard care in the phase III, randomized trial (ENZAMET) [8] (Table 1). In another double-blind, randomized trial (ARCHES), enzalutamide also revealed the benefit of rPFS (not-reached vs. 19 months, p < 0.001) in mHSPC patients [9] (Table 1). Regarding the safety and adverse effects of the drug, enzalutamide had the adverse effect to the central nervous system via entering the blood–brain barrier. Therefore, seizure and even posterior encephalopathy syndrome were reported in rare cases [2][7].

2. Apalutamide

Apalutamide is a second-generation androgen inhibitor and is already approved for use in nmCRPC and mHSPC. A double-blind, placebo-controlled, phase III trial (SPARTAN) demonstrated that apalutamide improved median metastasis-free survival compared with placebo (40.5 vs. 16.2 months. p < 0.001) in patients with non-mCRPC [10] (Table 1). Time to symptomatic progression was significantly longer with apalutamide than with placebo [10]. Another randomized phase III trial (TITAN), in the patients with mHSPC, apalutamide plus androgen deprivation therapy (ADT), significantly improved OS and rPFS compared with ADT plus placebo [11] (Table 1).
The adverse effects of interest include fracture, dizziness, and hypothyroidism. Compared with other androgen inhibitors with enzalutamide and darolutamide, skin rash was mostly found in apalutamide [2][10][11].

3. Darolutamide

Like other second-generation androgen inhibitors, darolutamide can inhibit AR translocation, DNA binding, and AR-mediated transcription (Figure 1). From the phase I/II study, darolutamide inhibited cell proliferation more efficiently than enzalutamide in a castration animal model [23]. Besides, it also blocks the activity of the mutant ARs like the F876L mutation caused by enzalutamide or apalutamide [23].
In a randomized, double-blind, placebo-controlled, phase III trial (ARAMIS), darolutamide improved metastasis-free survival (40.4 months vs. 18.4 months, p < 0.001) compared with placebo in patients with nmCRPC [12] (Table 1). Additionally, it also demonstrated benefit in OS, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event [12]. Another randomized, phase III trial (ARASENS), combination therapy with darolutamide, ADT, and docetaxel improve OS over placebo plus ADT and docetaxel in patients with mHSPC [24].
Generally, darolutamide causes less toxic effect because of low blood–brain barrier penetration and low binding affinity for γ-aminobutyric acid type A receptors due to its unique structure, which is different from enzalutamide and apalutamide. Therefore, it causes less central nervous system effect like a seizure [2][12]. The most reported adverse effects were fatigue and asthenic conditions [12].

4. Abiraterone

Abiraterone acetate is a selective CYP17 enzyme inhibitor that can decrease the synthesis of androgen of the testis, adrenal gland and prostate gland [25][26][27][28] (Figure 1). In the double-blind, placebo-controlled phase 3 study (CO-AA-301 clinical trial), it demonstrated that abiraterone combined with prednisolone improved OS compared to the placebo plus prednisolone group (15.8 vs. 11.2 months. p < 0.0001) in patients with metastatic CRPC (mCRPC) who progressed after chemotherapy [13] (Table 1). Another phase III study (CO-AA-302) further confirmed the benefit of abiraterone used in patients with mCPRC before chemotherapy. It improved rPFS and OS (34.7 months vs. 30.3 months) compared with placebo [14] (Table 1). The FDA approved the use of abiraterone in patients with mCRPC post-chemotherapy in 2011, subsequently, pre-chemotherapy based on these two phases III clinical trials in 2012. Furthermore, the FDA further approved the use of abiraterone in patients with high-risk mHSPC based on the phase III clinical trial (LATITUDE study) in 2018 [15][16] (Table 1). Abiraterone plus ADT and prednisolone improved OS and rPFS in patients with mHSPC compared with placebo plus ADT, because the use of abiraterone may cause the miner alocorticoid increase, which will cause fluid edema, liver function impairment, low potassium level, and high blood pressure [13][14][15]. Therefore, abiraterone must be used in combination with steroid, and regular follow-up of liver function and potassium level is necessary [13][14][15]. Previous study indicated that the E3 ubiquitin ligase adaptor speckle-type pox virus and zinc finger (POZ) protein (SPOP) are involved in controlling protein stability of AR by interacting with steroid receptor coactivator 3 (SRC-3) protein and some of the transcriptional coactivators [29]. Wild-type SPOP can promote the SRC-3 protein and then suppress AR transcriptional activity, thus functioning as a potential tumor suppressor [29]. However, some studies identified mutant SPOP in 6–15% of PCa and it can alleviate the tumor suppressive effect [30][31]. Surprisingly, PCa patients with mutant SPOP appear to delay the onset of ADT resistance to 42.0 (95% CI: 25.7–60.8) months. Also, the better outcomes in patients with mutant SPOP treated with abiraterone and enzalutamide were observed [32][33]. Therefore, it implies that SPOP mutation could enhance ADT effect by maintaining AR dependency. Inflammatory response is related to patients treated with ADT. It can cause a IL-6 increase through testosterone suppression [34] and disease progression to CRPC through the activation STAT3 pathway in PCa [35], because IL-6 is known to induce epithelial–mesenchymal transition (EMT) leading to PCa invasion [36]. It is warranted that inflammation factors can be of prognostic value in PCa progression [35].

References

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