Genomic profiling is increasingly used for routine clinical management of prostate cancer. Genomic profiling with NGS has revealed mCRPC to be heterogenous and has also made it feasible for personalized targeted therapy for specific biomarkers.7 In the current real-world study, olaparib showed remarkable clinical outcomes in Chinese patients with mCRPC, especially in patients harboring HRR gene aberrations. The results from the current study are in line with the earlier reports from larger prospective trials including the TOPARP-A, TOPARP-B and PROfound trial in which olaparib demonstrated prolonged radiologic progression-free survival (rPFS) in mCRPC patients with HRR mutations.11, 21 In the PROfound trial, the median rPFS was significantly longer in the patients with at least 1 aberration in HRR genes than in the control group (enzalutamide or abiraterone; rPFS: 5.8 months vs 3.5 months; HR: 0.49; 95% CI: 0.38–0.63; P<0.001). Further 43% (66/153) of patients carrying at least 1 aberration in the BRCA1/2 or ATM gene treated with olaparib had a PSA50 response while only 8% of patients in the control group had a PSA50 response.1
Several prospective genomic studies demonstrated that men with BRCA1/2 mutations have increased risk of early-onset and clinically significant prostate cancer.22–24 Furthermore, germline BRCA1/2 status is an independent prognostic factor for prostate cancer outcome, where patients carrying BRCA1/2 mutation are associated with high Gleason score, late TNM stage at diagnosis, early distant metastasis, and low 5-year survival.25 In a prospective cohort study (PROREPAIR-B), cause specific survival of mCRPC patients with BRCA1/2 mutation was significantly less (17.4m vs 33.2m, p=0.027) in comparison to patients with wild type after receiving standard therapy (abiraterone or doxetaxel).26 However, in the current study, mCRPC patients harboring BRCA2 mutations experienced superior clinical outcomes with olaparib monotherapy (PSA-PFS: 9.5 months, 95% CI: 4.3, NA) which was in accordance to another real-world study wherein patients harboring BRCA 1/2 gene variants had a significantly higher rate of PSA remission and longer PFS than those with variants in other HRR genes.27
Several studies substantiated that BRCA1/2 aberrations are a strong predictor of a favorable response to PARP inhibitors. But in case of prostate cancer, an increase in the frequency of the incidence of VUS in BRCA1/2 gene was reported.28 Since the effects of the VUS on the function of the encoded protein or disease risk is unknown, this poses a major challenge for genetic counseling and clinical management, which may require dynamic changes in the reporting of results for clinical decision making (“upgraded” to pathogenic or “downgraded” to benign).29–31 However, the findings from the current study demonstrated that patients harboring HRR VUS mutations exhibited a high PSA response rate and prolonged PSA-PFS after olaparib treatment, indicating that patients harboring HRR VUS mutations may benefit from olaparib treatment, which need further confirmation. There are several molecular- or cellular-level functional assays (such as cellular survival and viability assay, DNA recombination repair assay, genomic instability assay, and drug sensitivity assay) with high sensitivity and specificity that allow accurate assessment of the effects of VUS mutations on the encoded protein function.29,30,32 Despite considerable efforts to determine the pathogenicity of VUS mutations using multiple functional assays, for most VUS, this is not successful because of the lack of general consensus in clinical practice and evidence on the clinical efficacy of these mutations.31,33 To the best of our knowledge, this was the first study to emphasize on the clinical relevance of HRR VUS alterations in Chinese patients with mCRPC,; the findings from the current study may bring new evidence to the reclassification of VUS mutations in clinical practice and olaparib maybe considered for mCRPC patients carrying VUS alterations and without effective therapy regimen available.
Another interesting observation in the study is some patients exhibited prolonged survival benefits defined as PFS >1 year; the characteristic of these patients is listed in Table 3. Several common points are identified. Four patients carrying BRCA2 mutations (3 patients in the HRRm-positive group and 1 patient with HRR VUS defect) received olaparib and abiraterone combination therapy either as 2L or 3L therapy. In addition, in 1 patient (patient ID: WY) with HRR VUS alteration gATM p.Y171C, PSA level raised after 4 months of treatment and declined after 9 months and demonstrated lower PSA-PFS (4 months). However, the patient exhibited prolonged survival with olaparib treatment (overall survival: 38 months; Table 3). Although PARP inhibitors have demonstrated the clinical effectiveness in several kinds of tumors with underlying HRR deficiencies, there is now biologic and early clinical evidence to support their use in other molecular subsets of cancer, including DDR defects.34,35 At this juncture, another noteworthy finding was observed in our study: prolonged PSA-PFS (13 months) and PSA response were observed in a patient harboring DDR defect in the ATR loci (ATR p.K2106fs; Table 3), suggesting that other DDR gene aberrations may also confer sensitivity to olaparib treatment. The role of ATR in DNA repair pathway pertains to both single and double strand break repair.36 Mutations in ATR loci is rarely reported in clinical studies and a previous meta-analysis evaluating the role of DDR mutations in 77 genes reported a high number of studies with unknown ATR gene status.37,38 Recently, a mounting body of evidence from in vitro and in vivo studies indicates that PARP inhibitors in combination ATR inhibitors can be used across a wide spectrum of cancers, and these findings lead to early-phase clinical trials combining ATR and PARP inhibitors (NCT02576444, NCT02723864, NCT03787680 [TRAP-trial], and NCT03682289).39 However, larger prospective trials are required to substantiate the effectiveness of PARP inhibitors in subset of patients with other DDR defects.
Table 3
Patient Characteristics and Clinical Outcomes of Patient Exhibiting Prolonged Survival Benefits
Patient ID
|
RJ119
|
SY4
|
SY5
|
RJ62
|
WY
|
RJ103
|
Age (years)
|
42
|
59
|
70
|
61
|
69
|
70
|
PSA at diagnosis
|
>100
|
11.92
|
30
|
55
|
unknown
|
>100
|
Gleason score
|
9
|
10
|
9
|
8
|
9
|
8
|
Distant metastasis at first diagnosis
|
Multiple bone metastases
|
Multiple lymph nodes metastases
|
Multiple bone metastases
|
Multiple bone metastases
|
Multiple bone metastases
|
Multiple bone metastases
|
ADT treatment duration (months)
|
12
|
1
|
7
|
60
|
9
|
48
|
mCRPC 1L
|
Abiraterone
|
Docetaxel
|
Abiraterone
|
Abiraterone
|
Enzalutamide
|
Abiraterone
|
1L PSA-PFS
|
unknown
|
Primary resistant
|
5.7
|
10
|
NO effect
|
12
|
mCRPC 2L
|
Abiraterone + olaparib
|
Radiotherapy + abiraterone
|
Docetaxel
|
Docetaxel
|
Docetaxel
|
Olaparib
|
2L PSA-PFS
|
16
|
Unknown
|
4
|
2
|
Unknown
|
13
|
mCRPC 3L
|
NA
|
Abiraterone + olaparib
|
Abiraterone + olaparib
|
Olaparib
|
Olaparib
|
|
PSA-PFS (m)
|
16*
|
30*
|
21.4
|
16
|
4
|
13
|
PSA response rate
|
−89.5%
|
Unknown
|
Unknown
|
−32%
|
−70.6%
|
−62.2%
|
Overall survival (m)
|
16*
|
30*
|
27.4
|
39.5
|
38
|
Unknown
|
Mutation sites
|
gBRCA2 splicing
|
BRCA2:p.K2849fs
|
BRCA2p.Q1551K (0.5%)
|
BRCA2:p.N1784fs
|
gATM p.Y171C
|
ATR p.K2106fs (0.72%)
|
Biomarker status
|
HRRm positive
|
HRRm positive
|
HRR VUS
|
HRRm positive
|
HRR VUS
|
DDR defect
|
ADT, androgen deprivation therapy; DDR, DNA damage repair; HRR, homologous recombination repair; mCRPC: metastatic castration-resistant prostate cancer; NA, not available; PSA-PFS, prostate-specific antigen progression-free survival; VUS, variants of uncertain significance.
PSA-PFS and overall survival were calculated from the starting of olaparib treatment to the end of follow-up, * indicated that patients were in progress-free status or alive until the end of follow-up.
|
Despite these interesting findings, our study has certain limitations. First, the retrospective nature as well as relatively small sample size limit the interpretation of the negative results. Second, lack of overall survival and safety data that indicate that systemic and intense follow-up system need to be established in the future.