Castration-Resistant Prostate Cancer: Comparison
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Please note this is a comparison between Version 2 by Vicky Zhou and Version 1 by Jeremy Yuen Chun Teoh.

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 investigTationabl treatment modalitiese 2. 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

References

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