Table 1 Current standard (approved) therapies and tested new immunotherapies for castration-resistant prostate cancer

Abiraterone acetate

Yes

Androgen synthetic inhibitor

mOS abiraterone acetate + prednisone versus placebo + prednisone group: 34.7 months (95% CI, 32.7–36.8) versus 30.3  months (28.7–33.3); HR, 0.81 (95% CI, 0.70–0.93; P < 0.0033)

Yes. Abiraterone acetate + prednisone versus placebo: grade 3–4: hypertension 5% versus 3%; hypokalaemia 2% versus 2%; serious AEs of any grade: 38% versus 27%; serious AE hypokalaemia: <1% versus 0; treatment-related deaths: 0% versus  0%

[56]

Enzalutamide

Yes

Androgen receptor inhibitor

mOS enzalutamide versus placebo group: 67.0 months (95% CI, 64.0–NR) versus 56.3 months (95% CI, 54.4–63.0); HR, 0.73 (95% CI, 0.61–0.89; P = 0.001)

Yes. Grade ≥ 3 the exposure-adjusted rate of AEs in the enzalutamide versus placebo group: 17/100 patient-years versus 20/100 patient-years. Most frequently reported AE in the enzalutamide group: fatigue and musculoskeletal events

[29, 57]

Apalutamid

Yes

Androgen receptor inhibitor

mMFS apalutamide versus placebo group: 40.5 months versus 16.2 months; HR for metastasis or death, 0.28 (95% CI, 0.23–0.35; P < 0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo; HR, 0.45 (95% CI, 0.32–0.63; P < 0.001)

Yes. The rate of AE leading to discontinuation of the trial regimen: apalutamide versus placebo group: 10.6% versus 7.0%. AEs occurred at a higher rate with apalutamide than with placebo: rash (23.8% versus 5.5%), hypothyroidism (8.1% versus 2.0%), fracture (11.7% versus 6.5%)

[31]

Darolutamid

Yes (FDA)

Androgen receptor inhibitor

3-year OS darolutamide versus placebo: 83% (95% CI, 80–86) versus 77% (95% CI, 72 to 81). The risk of death was significantly lower, by 31%, in the darolutamide group than in the placebo group; HR for death, 0.69 (95% CI, 0.53–0.88; P = 0.003). Darolutamide was associated with a significant benefit with respect to the time to first symptomatic skeletal event and the time to first use of cytotoxic chemotherapy

No. The incidence of AEs after the start of treatment was similar in the two groups; no new safety signals were observed

[30, 58]

Docetaxel

Yes

Chemotherapeutic drug

Docetaxel + estramustine versus mitoxantrone and prednisone: mOS: 17.5 months versus 15.6 months, P = 0.02; HR, 0.80 (95% CI, 0.67–0.97). mPFS: 6.3 months versus 3.2 months (P < 0.001). ≥ PSA decline: 50% versus 27% (P < 0.001). Objective tumour responses: 17% versus 11% (P = 0.30)

Yes. Grade 3 or 4 more common in docetaxel + estramustine versus mitoxantrone + prednisone group: neutropenic fevers, (P = 0.01), nausea and vomiting (P < 0.001), cardiovascular events (P = 0.001)

[59]

Cabazitaxel

Yes

Chemotherapeutic drug

Cabazitaxel versus androgen-signalling-targeted inhibitor: imaging-based progression or death: 73.6% versus 80.2%; HR, 0.54 (95% CI, 0.40–0.73; P < 0.001). mPFS (imaging-based): 8.0 versus 3.7 months. mOS: 13.6 versus 11.0 months; HR, 0.64 (95% CI, 0.46–0.89; P = 0.008). mPFS 4.4 versus 2.7 months; HR, 0.52 (95% CI, 0.40–0.68; P < 0.001). PSA response: 35.7% versus 13.5% (P < 0.001). Tumour response: 36.5% versus 11.5% (P = 0.004)

Yes/no. Cabazitaxel versus androgen-signalling-targeted inhibitor: grade ≥ 3 AE: 56.3% versus 52.4%; no new safety signals were observed

[60]

Olaparib

Yes (FDA)

PARP inhibitor

Olaparib versus enzalutamide or abiraterone: rPFS: 7.4 months versus 3.6 months (HR, 0.34; 95% CI, 0.25–0.47; P < 0.001), confirmed ORR 33% versus 2% (OR 20.86, 95% CI, 4.18–379.18: P < 0.001). mOS: 18.5 months versus 15.1 months (in pts with BRCA1/2, ATM alterations), (HR, 0.64, 95% CI, 0.43–0.97; P = 0.02)

Yes. The incidence of AEs of grade 3 or higher was higher with olaparib than with the control treatment. The most common AEs: anemia, nausea, and fatigue or asthenia with olaparib and fatigue or asthenia with the control treatment. A total of 11 cases of pulmonary embolism (4% of patients) were reported in the olaparib group, as compared with 1 (1%) in the control group; none were fatal

[61]

Sipuleucel-T

Yes (FDA)

Cell-based immunotherapy

Sipuleucel-T versus placebo group: relative risk reduction of death, 22%; HR, 0.78 (95% CI, 0.61–0.98; P = 0.03). mOS: 25.8 versus 21.7 months. 3-year survival probability: 31.7% versus 23.0%; HR, 0.77 (95% CI, 0.61–0.97; P = 0.02). Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T

Yes. AEs more frequently reported in the sipuleucel-T group: chills, fever, headache

[22, 62]

Ipilimumab

No

Immune check-point inhibitor

No. Ipilimumab versus placebo: mOS: 28.7 months (95% CI, 24.5–32.5) versus 29.7 months (95% CI, 26.1–34.2); HR, 1.11 (95.87% CI, 0.88–1.39; P = 0.367). mPFS: 5.6 versus 3.8 months; HR, 0.67 (95.87% CI, 0.55–0.81). PSA response rate: 23% versus 8%

Yes. Grade 3–4 treatment-related AEs reported in ≥ 10% of ipilimumab-treated patients: diarrhoea (15%). Ipilimumab versus placebo: deaths, 2% versus 0; immune-related grade 3–4 AEs: 31% versus 2%

[32]

aHyC

Non-routine, hospital exemption

DC-tumour immunohybridoma

mOS: 58.5 months (95% CI, 38.8–78.2). mCSS: 75.7 months (95% CI, 41.1–110.4)

No. Only grade 1 treatment-related AEs (e.g., asthenia, pelvic pain, rush)

[12]

Pembrolizumab

Yes (FDA)

Immune check-point inhibitor

mrPFS 2.1 months (95% CI, 2.1–2.2). mOS 9.6 months (95% CI, 7.9–12.2)

Yes. Grade 3–5 treatment-related AEs: 15% patients. Discontinuation of pembrolizumab because of a treatment-related AE: 5% patients. Deaths due to treatment-related AEs: 0.8% (n = 2, pneumonitis and sepsis). The most common treatment-related AEs: fatigue, diarrhoea, decreased appetite. Immune-mediated AEs and infusion reactions: 16% patients (grade 3–5 in 6% patients; led to discontinuation in 2% patients and death in < 1%). The most common immune-mediated AEs were colitis, hyperthyroidism, hypothyroidism, pneumonitis, and severe skin reactions

[33, 63,64,65]