World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://www.wjon.org

Original Article

Volume 14, Number 6, December 2023, pages 518-528

Addition of Olaparib to the New Hormonal Agent Regimen for Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis

Figure 2. Summary of risk of bias (RoB) assessment of the included studies. All bias variables disclosed as low risk of bias.

Figure 3. (a) Progression-free survival (PFS) as presented in pooled metastatic castration-resistant prostate cancer (mCRPC) and mutated homologous recombinant repair (mHRR)/ataxia-telangiectasia mutated (mATM) populations. (b) Pooled overall survival (OS) analysis of the included study.

**Table 1.** Summary and Characteristics of the Included Studies
Study and design	Criteria of eligibility	Treatment settings	Intervention (olaparib-regimen)	Comparison	Maximum trial follow-up (months)	Outcomes
RCT: randomized controlled trial; mCRPC: metastatic castration-resistant prostate cancer; ADT: androgen deprivation therapy; CT: computed tomography; MRI: magnetic resonance imaging; mHSPC: metastatic hormone-sensitive prostate cancer.
Clarke 2018 (open-label RCT phase II)	Males ≥ 18 years old or older; Histologically or cytologically confirmed mCRPC	Patients with previous taxanes treatment were allowed	Olaparib (300 mg) PO bd + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd	Placebo + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd	30	Progression-free survival, overall survival, adverse events
Clarke 2022 (RCT phase III)	Male ≥ 18 years old or older (≥ 19 years in South Korea centers); Histologically or cytologically confirmed CRPC; At least one documented metastatic lesion on a bone scan or CT or MRI scan	First-line treatment after mCRPC confirmation (except for ADT); Prior docetaxel during neoadjuvant/adjuvant treatment for mHSPC	Olaparib (300 mg) PO bd + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd	Placebo + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd	31	Progression-free survival, overall survival, adverse events
PROfound: De Bono 2020 (open-label RCT phase III)	Male ≥ 18 years old or older; Histologically or cytologically confirmed mCRPC	Administered with docetaxel as well for treating the current mCRPC	Olaparib (300 mg) PO bd + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd	Placebo + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd	31	Progression-free survival, overall survival, adverse events

Table 1. Summary and Characteristics of the Included Studies

Study and design

Criteria of eligibility

Treatment settings

Intervention (olaparib-regimen)

Comparison

Maximum trial follow-up (months)

Outcomes

RCT: randomized controlled trial; mCRPC: metastatic castration-resistant prostate cancer; ADT: androgen deprivation therapy; CT: computed tomography; MRI: magnetic resonance imaging; mHSPC: metastatic hormone-sensitive prostate cancer.

Clarke 2018 (open-label RCT phase II)

Males ≥ 18 years old or older; Histologically or cytologically confirmed mCRPC

Patients with previous taxanes treatment were allowed

Olaparib (300 mg) PO bd + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd

Placebo + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd

Progression-free survival, overall survival, adverse events

Clarke 2022 (RCT phase III)

Male ≥ 18 years old or older (≥ 19 years in South Korea centers); Histologically or cytologically confirmed CRPC; At least one documented metastatic lesion on a bone scan or CT or MRI scan

First-line treatment after mCRPC confirmation (except for ADT); Prior docetaxel during neoadjuvant/adjuvant treatment for mHSPC

Olaparib (300 mg) PO bd + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd

Placebo + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd

Progression-free survival, overall survival, adverse events

PROfound: De Bono 2020 (open-label RCT phase III)

Male ≥ 18 years old or older; Histologically or cytologically confirmed mCRPC

Administered with docetaxel as well for treating the current mCRPC

Olaparib (300 mg) PO bd + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd

Placebo + abiraterone (1,000 mg) PO qd + prednisone/prednisolone (5 mg) PO bd

Progression-free survival, overall survival, adverse events

**Table 2.** The Characteristics of Populations Included in Each Trial
Study/arm (n)	Age (years)	ECOG performance status ≥ 1 (%)	Metastasis status and number of bone metastases at the baseline (%)	Prior treatment (%)	PSA concentration at the baseline (µg/L)	Confirmed HRR mutation and BRCA status (%)
ECOG: Eastern Cooperative Oncology Group; PSA: prostate-specific antigen; HRR: homologous recombinant repair; NHA: new hormonal agent.
Clarke 2018	Olaparib (71)	70 (65 - 75)	52.1	Bone disease only (46.5); Soft-tissue disease only (11.3); Bone and soft-tissue disease (42.3); Number of participants with bone metastasis sites > 1 (88.7)	Docetaxel (100.0); Cabazitaxel (14.1)	86.0 (23 - 194)	HRR mutation (15.5)
	Control (71)	67 (62 - 74)	43.6	Bone disease only (46.5); Soft-tissue disease only (15.5); Bone and soft-tissue disease (38.0); Number of participants with bone metastasis sites > 1 (85.9)	Docetaxel (100.0); Cabazitaxel (12.7); Abiraterone (1.4)	47.0 (21 - 199)	HRR mutation (14.1)
Clarke 2022	Olaparib (399)	69 (43 - 91)	28.1	Bone-related (87.5); Distant lymph nodes (33.3); Locoregional lymph nodes (20.6); Prostate and adjacent structure (11.8); Respiratory (including lung) (10.6); Liver (3.8)	Docetaxel (46.9); NHA (0.3)	17.9 (6.1 - 67.0)	HRR mutation (27.8); BRCA1 (2.3); BRCA2 (9.5)
	Control (397)	70 (46 - 88)	31.2	Bone-related (85.4); Distant lymph nodes (30.0); Locoregional lymph nodes (22.4); Prostate and adjacent structure (11.6); Respiratory (including lung) (10.6); Liver (4.5)	Docetaxel (46.9); NHA (0.3)	16.8 (6.3 - 53.3)	HRR mutation (27.8); BRCA1 (2.3); BRCA2 (9.5)
De Bono 2020	Olaparib (256)	69 (47 - 91)	48.8	Bone disease only (33.6); Lung or liver (26.6); Other (34.4)	NHA (100.0); Taxanes (66.4)	68.2 (24.1 - 294.4)	BRCA1 (3.1); BRCA2 (31.6)
	Control (131)	69 (49 - 87)	57.3	Bone disease only (29.0); Lung or liver (33.6); Other (31.3)	NHA (100.0); Taxanes (66.4)	106.5 (37.2 - 326.6)	BRCA1 (3.8); BRCA2 (35.9)

Table 2. The Characteristics of Populations Included in Each Trial

Study/arm (n)

Age (years)

ECOG performance status ≥ 1 (%)

Metastasis status and number of bone metastases at the baseline (%)

Prior treatment (%)

PSA concentration at the baseline (µg/L)

Confirmed HRR mutation and BRCA status (%)

ECOG: Eastern Cooperative Oncology Group; PSA: prostate-specific antigen; HRR: homologous recombinant repair; NHA: new hormonal agent.

Clarke 2018

Olaparib (71)

70 (65 - 75)

52.1

Bone disease only (46.5); Soft-tissue disease only (11.3); Bone and soft-tissue disease (42.3); Number of participants with bone metastasis sites > 1 (88.7)

Docetaxel (100.0); Cabazitaxel (14.1)

86.0 (23 - 194)

HRR mutation (15.5)

Control (71)

67 (62 - 74)

43.6

Bone disease only (46.5); Soft-tissue disease only (15.5); Bone and soft-tissue disease (38.0); Number of participants with bone metastasis sites > 1 (85.9)

Docetaxel (100.0); Cabazitaxel (12.7); Abiraterone (1.4)

47.0 (21 - 199)

HRR mutation (14.1)

Clarke 2022

Olaparib (399)

69 (43 - 91)

28.1

Bone-related (87.5); Distant lymph nodes (33.3); Locoregional lymph nodes (20.6); Prostate and adjacent structure (11.8); Respiratory (including lung) (10.6); Liver (3.8)

Docetaxel (46.9); NHA (0.3)

17.9 (6.1 - 67.0)

HRR mutation (27.8); BRCA1 (2.3); BRCA2 (9.5)

Control (397)

70 (46 - 88)

31.2

Bone-related (85.4); Distant lymph nodes (30.0); Locoregional lymph nodes (22.4); Prostate and adjacent structure (11.6); Respiratory (including lung) (10.6); Liver (4.5)

Docetaxel (46.9); NHA (0.3)

16.8 (6.3 - 53.3)

HRR mutation (27.8); BRCA1 (2.3); BRCA2 (9.5)

De Bono 2020

Olaparib (256)

69 (47 - 91)

48.8

Bone disease only (33.6); Lung or liver (26.6); Other (34.4)

NHA (100.0); Taxanes (66.4)

68.2 (24.1 - 294.4)

BRCA1 (3.1); BRCA2 (31.6)

Control (131)

69 (49 - 87)

57.3

Bone disease only (29.0); Lung or liver (33.6); Other (31.3)

NHA (100.0); Taxanes (66.4)

106.5 (37.2 - 326.6)

BRCA1 (3.8); BRCA2 (35.9)

**Table 3.** Meta-Analysis of Adverse Effects in Hematological and Non-Hematological System of This Study (All Studies Included)
Adverse effects	All grades, % (n/total)	Grade ≥ 3, % (n/total)
*Statistically significant based on the respective analysis model. CI: confidence interval; CtS: corticosteroid; NHA: new hormonal agent; RR: risk ratio; UTI: urinary tract infection.
Hematological
Anemia	44.7 (324/725)	14.4 (86/597)	3.16 (2.06 - 4.84)	< 0.05*	17.9 (130/725)	3.5 (21/597)	4.64 (2.96 - 7.28)	< 0.05*
Non-hematological
Nausea	33.8 (245/725)	15.1 (90/597)	2.13 (1.71 - 2.64)	< 0.05*	0.7 (5/725)	0.5(3/597)	1.05 (0.23 - 4.92)	> 0.05*
Decreased appetite	20.3 (147/725)	8.5 (51/597)	2.05 (1.53 - 2.76)	< 0.05*	1.0 (7/725)	0.2(1/597)	2.95 (0.50 - 17.57)	> 0.05*
Diarrhea	18.5 (134/725)	8.9 (53/597)	2.02 (1.48 - 2.74)	< 0.05*	0.7 (5/725)	0.3(2/597)	1.67 (0.35 - 8.08)	> 0.05*
Vomiting	15.7 (114/725)	10.2 (61/597)	1.49 (1.11 - 2.00)	< 0.05*	3.4 (25/725)	0.5 (3/597)	5.92 (1.77 - 19.82)	< 0.05*
Constipation	18.2 (132/725)	13.7 (82/597)	1.33 (1.01 - 1.74)	< 0.05*	0.0 (0/725)	0.2 (1/597)	0.33 (0.01 - 8.12)	> 0.05*
Fatigue	37.0 (268/725)	27.3 (163/597)	1.31 (1.12 - 1.55)	< 0.05*	2.3 (17/725)	2.5 (15/597)	0.82 (0.38 - 1.78)	> 0.05*
UTI	9.4 (68/725)	8.2 (49/597)	1.15 (0.81 - 1.62)	> 0.05*	1.8 (13/725)	1.8 (11/597)	0.92 (0.43 - 1.99)	> 0.05*
Peripheral edema	11.9 (86/725)	10.1 (63/597)	1.14 (0.83 - 1.56)	> 0.05*	0.0 (0/725)	0.2 (1/597)	0.33 (0.01, 8.12)	> 0.05*
Back pain	16.7 (121/725)	17.1 (102/597)	1.02 (0.80 - 1.30)	> 0.05*	0.8 (6/725)	1.0 (7/725)	0.69 (0.23 - 2.06)	> 0.05*
Arthralgia	11.4 (83/725)	14.7 (88/597)	0.85 (0.57 - 1.28)	> 0.05*	0.1 (1/725)	0.5 (3/597)	0.45 (0.07 - 2.76)	> 0.05*

Table 3. Meta-Analysis of Adverse Effects in Hematological and Non-Hematological System of This Study (All Studies Included)

Adverse effects

All grades, % (n/total)

Grade ≥ 3, % (n/total)

Olaparib plus SC (NHA + CtS)

SC (NHA + CtS) only

RR (95% CI)

P value

Olaparib plus SC (NHA + CtS)

SC (NHA + CtS) only

RR (95% CI)

P value

*Statistically significant based on the respective analysis model. CI: confidence interval; CtS: corticosteroid; NHA: new hormonal agent; RR: risk ratio; UTI: urinary tract infection.

Hematological

Anemia

44.7 (324/725)

14.4 (86/597)

3.16 (2.06 - 4.84)

< 0.05*

17.9 (130/725)

3.5 (21/597)

4.64 (2.96 - 7.28)

< 0.05*

Non-hematological

Nausea

33.8 (245/725)

15.1 (90/597)

2.13 (1.71 - 2.64)

< 0.05*

0.7 (5/725)

0.5(3/597)

1.05 (0.23 - 4.92)

> 0.05*

Decreased appetite

20.3 (147/725)

8.5 (51/597)

2.05 (1.53 - 2.76)

< 0.05*

1.0 (7/725)

0.2(1/597)

2.95 (0.50 - 17.57)

> 0.05*

Diarrhea

18.5 (134/725)

8.9 (53/597)

2.02 (1.48 - 2.74)

< 0.05*

0.7 (5/725)

0.3(2/597)

1.67 (0.35 - 8.08)

> 0.05*

Vomiting

15.7 (114/725)

10.2 (61/597)

1.49 (1.11 - 2.00)

< 0.05*

3.4 (25/725)

0.5 (3/597)

5.92 (1.77 - 19.82)

< 0.05*

Constipation

18.2 (132/725)

13.7 (82/597)

1.33 (1.01 - 1.74)

< 0.05*

0.0 (0/725)

0.2 (1/597)

0.33 (0.01 - 8.12)

> 0.05*

Fatigue

37.0 (268/725)

27.3 (163/597)

1.31 (1.12 - 1.55)

< 0.05*

2.3 (17/725)

2.5 (15/597)

0.82 (0.38 - 1.78)

> 0.05*

UTI

9.4 (68/725)

8.2 (49/597)

1.15 (0.81 - 1.62)

> 0.05*

1.8 (13/725)

1.8 (11/597)

0.92 (0.43 - 1.99)

> 0.05*

Peripheral edema

11.9 (86/725)

10.1 (63/597)

1.14 (0.83 - 1.56)

> 0.05*

0.0 (0/725)

0.2 (1/597)

0.33 (0.01, 8.12)

> 0.05*

Back pain

16.7 (121/725)

17.1 (102/597)

1.02 (0.80 - 1.30)

> 0.05*

0.8 (6/725)

1.0 (7/725)

0.69 (0.23 - 2.06)

> 0.05*

Arthralgia

11.4 (83/725)

14.7 (88/597)

0.85 (0.57 - 1.28)

> 0.05*

0.1 (1/725)

0.5 (3/597)

0.45 (0.07 - 2.76)

> 0.05*