Castration-Resistant Prostate Cancer

Castration-Resistant Prostate Cancer: History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Subjects: Oncology

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Castration-resistant prostate cancer (CRPC) is defined as castrate serum testosterone levels (<50 ng/dL or 1.7 nmol/L) plus either biochemical or radiological progression, as specified in the European Association of Urology guidelines.

prostate cancer
castration resistance
androgen deprivation therapy

1. Introduction

Castration-resistant prostate cancer (CRPC) can take place in both non-metastatic and metastatic settings. The differentiation between non-metastatic CRPC (M0CRPC) and metastatic disease (mCRPC) is by conventional imaging, i.e., computed tomography (CT) and bone scan ^[1]. Furthermore, a prostate specific antigen-doubling time (PSA-DT) of less than 10 months is associated with a higher risk of bone metastases or death ^[2]. The median survival in mCRPC is approximately 35 months, depending on different prognostic factors and the use of second- and third-line systematic treatment ^[3].

Moreover, positron emission tomography of ⁶⁸Ga-labelled prostate-specific membrane antigens (PSMA-PET) is a promising imaging modality in advanced prostate cancer. A systematic review studied the diagnostic accuracy of PSMA-PET performed in 1309 patients with advanced prostate cancer ^[4]. The sensitivity and specificity were both 86% on a per-patient basis. With the increased use of PSMA-PET, the accuracy for diagnosing early metastasis is expected to improve in the CRPC population.

For oligometastasis in hormone-sensitive and recurrent prostate cancer (typically defined as three or fewer metastases), the potential benefits of the primary tumor treatment and/or metastasis-directed therapy were explored ^[5]. Similarly, several retrospective studies suggested that ablative radiotherapy or surgery of oligometastases in CRPC might delay the PSA progression and the initiation of the next-line systematic treatment ^[6]^[7]. In this sense, oligometastatic CRPC appeared to be a distinct entity that warrants further investigations on its prognostic significance and implications on treatment strategies.

2. Treatment Options for M0CRPC and mCRPC

2.1. Treatment Options for M0CRPC

Three large randomized controlled trials (RCT), SPARTAN ^[8], PROSPER ^[9], and ARAMIS ^[10], evaluated the metastasis-free survival (MFS) as the primary end-point in patients with non-metastatic CRPC (M0CRPC) treated with enzalutamide (PROSPER), apalutamide (SPARTAN), and darolutamide (ARAMIS) against placebo, respectively. CT and bone scans were used in these trials to diagnose the non-metastatic status of the disease. Of note, only patients with a short PSA doubling time of fewer than 10 months were included. ADT was continuously used in both the novel agent arms and the placebo arms. MFS was defined as the time to the first metastasis on imaging or death.

Enzalutamide bound to AR with higher affinity than androgens, thereby inhibiting downstream nuclear translocation and DNA binding ^[9]. Apalutamide was another competitive AR inhibitor that reduced AR-mediated cancer growth ^[8]. Darolutamide shared similar mechanisms and had special chemical characteristics which prevented the drug from entering the blood-brain barrier ^[10].

In all of these trials, a significant MFS benefit was observed. Apalutamide yielded a median MFS of 40.5 months, compared to 16.2 months in the placebo group (homologous recombination (HR) 0.28; 95% CI: 0.23–0.35; p < 0.001) ^[8]. Enzalutamide gave a median MFS of 36.6 months vs. 14.7 months in the placebo arm (HR 0.29; 95% CI: 0.24–0.35; p < 0.001) ^[9]. Darolutamide was shown to have a median MFS of 40.4 months, compared to 18.4 months in the placebo group (HR 0.41; 95% CI: 0.34–0.50; p < 0.0001) ^[10].

The updated results of these trials presented in the 2020 American Society of Oncology (ASCO) meeting showed a significant overall survival (OS) benefit. In PROSPER, the median OS for the enzalutamide group was 67 months, compared to 56 months in the placebo group (HR 0.73; 95% CI: 0.61–0.89; p = 0.001). The benefit of enzalutamide was generally consistent across prespecified subgroups, with the potential exception of a small group of patients receiving bone-sparing agents ^[11]. In SPARTAN, apalutamide gave a better median OS than the placebo (73.9 vs. 59.9 months), corresponding to a relative reduction of 21.6% in the risk of mortality (HR 0.78; p = 0.0161) ^[12]. As for ARAMIS, with a median follow-up of 29 months, the 3-year OS rates were 83% and 77% on the darolutamide and placebo arms, respectively (HR 0.69; 95% CI: 0.53–0.88; p = 0.003). Notably, the use of darolutamide also significantly postponed the time of symptomatic bone events and the use of chemotherapy ^[13] compared to the placebo.

According to the above trials, these oral agents were generally well tolerated, with a treatment cessation due to adverse events in 9% for enzalutamide and darolutamide and 13.6% for apalutamide. Common side effects include fatigue (33% for enzalutamide, 31.9% for apalutamide, 16% for darolutamide), fall (11% for enzalutamide, 20.9% for apalutamide, 4% for darolutamide) and rashes (Not reached for enzalutamide, 24% for apalutamide, 3% for darolutamide). The clinical benefits and safety profiles of these drugs are summarized in Table 1.

Table 1. Summary of non-metastatic castration-resistant prostate cancer (M0CRPC) treatment options.

Study	SPARTAN ^[8]	PROSPER ^[9]	ARAMIS ^[10]
Agent	Apalutamide	Enzalutamide	Darolutamide
Dosage	240 mg daily	160 mg daily	600 mg BD with food
MFS (months)	40.5 vs. 16.2 HR 0.28; p < 0.0001	36.6 vs. 14.7 HR 0.29; p < 0.001	40.4 vs. 18.4 HR 0.41; p < 0.0001
Updated OS (months)	73.9 vs. 59.9 HR 0.78; p = 0.016	67 vs. 56.3 HR 0.73; p = 0.001	83 vs. 77 HR 0.69; p = 0.003
Adverse event (AE) reporting	Every 1 month	Every 4 months	Every 4 months
Grade ¾ AE (%)	53	31	25
Fatigue (%)	31.9	33	16
Fall (%)	20.9	11	4
Rash (%)	24	NR	3
Treatment cessation due to AE (%)	13.6	9	9

OS, significant overall survival; HR, homologous recombination; NR, not reached; MFS, metastasis-free survival.

2.2. Treatment Options for mCRPC

In the past, older-generation antiandrogens such as bicalutamide were the standard approach to treating mCRPC. Recent phase 3 studies, however, demonstrated better clinical outcomes for the use of chemotherapy (docetaxel and cabazitaxel), novel hormonal agents (abiraterone acetate and enzalutamide), Sipuleucel-T, Radium-223, and olaparib. Their key eligibility criteria and survival benefits are summarized in Table 2. Other investigational treatment modalities will also be discussed.

Table 2. Summary of established metastatic castration-resistant prostate cancer (mCRPC) treatment options.

Study	Agent	Control	Sample Size	Indication	HR	OS Benefit (months)
TAX-327 ^[14]	Docetaxel + Prednisolone	Mitoxantrone + Prednisolone	1006	mCRPC, symptomatic or not	0.76	2.9
IMPACT ^[15]	Sipuleucel-T	Placebo	512	mCRPC (pre-chemotherapy) mild/no symptoms, no visceral metastasis	0.78	4.1
COU-AA-302 ^[16]	Abiraterone + Prednisolone	Prednisolone	1088	mCRPC (pre-chemotherapy) mild/no symptoms, no visceral metastasis	0.81	NR
COU-AA-301 ^[17]	Abiraterone + Prednisolone	Prednisolone	1195	mCRPC (post-chemotherapy)	0.74	4.6
PREVAIL ^[18]	Enzalutamide	Placebo	1717	mCRPC (pre-chemotherapy)	0.77	4.0
AFFIRM ^[19]	Enzalutamide	Placebo	1199	mCRPC (post-chemotherapy)	0.63	4.8
TROPIC ^[20]	Cabazitaxel + Prednisolone	Mitoxantrone + Prednisolone	755	mCRPC (post-chemotherapy)	0.70	2.4
ALSYMPCA ^[21]	Radium-223	Placebo	921	mCRPC (post- or unfit for chemotherapy)	0.70	3.6
PROFOUND ^[22]	Olaparib	Enzalutamide or Abiraterone	387	mCRPC disease progression after either enzalutamide or abiraterone	0.34	N/A

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines9040339

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