Table 1.
Published clinical studies in metastatic castration-resistant prostate cancer (mCRPC) patients exploring the correlation between DNA damage repair (DDR) pathways and single-agent therapies with androgen receptor-signaling inhibitors (ARSi), poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitor (PARPi), immune checkpoint inhibitors (ICI), and prostate-specific membrane antigen inhibitors (PSMAi).
| Drug | Exploratory analysis | N | Design | Phase | Findings [Ref] |
|---|---|---|---|---|---|
| ARSi Abi./Enza. | Sequencing of 73 PCa genes |
319 | R | NA | 7.5% of pts with germline mutations (> BRCA2) → 3.3 mo mPSA progression [14] |
| ARSi Abi./Enza. | WES of 72 driver PCa genes |
202 | R | NA | BRCA2/ATM defective → shorter TTP [15] |
| ARSi Abi./Enza. | Search of gDDRgm | 390 | R | NA | Carriers vs. non-carriers: no difference as PFS and RR [16] |
| ARSi Abi./Enza. | Search of gDDRm in 50 genes |
172 | R | NA | BRCA/ATM mutations → better survival [17] |
| ARSi Abi./Enza.vs Taxanes | Search of gDDRm in 107 genes |
419 | P | 2 | BRCA2 mutations → better CSS (outcome maintained comparing ARSi vs. Taxanes) [18] |
| PARPi Olaparib | Search of BRCA1/2 mutation |
60 | P | 1 | 22 pts with BRCA1/2 mutation: benefit on Olaparib [5] |
| PARPi Olaparib (TOPARP-A) |
WES; transcriptome analysis | 50 | P | 2 | 14 out of 16 responders had DDR defects [19] |
| PARPi Rucaparib (TRITON2) |
Mandatory non-BRCA DDR gene defects |
78 | P | 2 | ATM, CDK12, CHEK2: <10% response. PALB2, RAD51B: better and lasting response [20] |
| PARPi Olaparib (TOPARP-B) |
Screening for DDR gene defects |
700 | P | 2 | 98 mutated pts received Olaparib 400/300 mg: 54%/39% tumor response [6] |
| PARPi Olaparib | Gene defects and response |
23 | R | NA | BRCA1/2 vs. ATM: 12 vs. 2 mo mPFS [21] |
| Olaparib vs Abi./Enza. (PROfound) |
HR DDRgm: A (BRCA1/2 or ATM), B (other genes) |
387 | P | 3 | Cohort A: mr-PFS (pe): 7.4 vs. 3.6 (p < 0.001) Cohorts A and B: mr-PFS: 5.8 vs. 3.5 (p < 0.001) [22] |
| Anti-PD-1 Pembrolizumab | MMR deficiency | 86 | P | 2 | 50% of responders (21 CR) [9] |
| Anti-PD-1/PD-L1 therapy | Molecular tumor profile |
1033 | R | NA | 3.1% of pts had MSI/MMR deficiency→ 6/11 had responses [23] |
| PSMA ADC | PSMA expression on CTC, NE markers | 119 | P | 2 | Chemo-group: 61% SDChemo-naive group: 69% SD, 6% PR 7-mo OS: 92% for both the two groups [24] |
Abbreviations: DDR, DNA damage repair; Ref., references; N, size; D, design; ARSi, androgen receptor signaling inhibitor; Abi., abiraterone acetate; Enza., enzalutamide; PCa, prostate cancer; mCRPC, metastatic castration-resistant prostate cancer; R, retrospective; NA, not applicable; pts, patients; mo, months; WES, whole-exome sequencing; P, prospective; TTP, time to progression; gDDRgm, germline DNA damage repair gene mutation; PFS, progression-free survival; RR, response rate; CSS, cause-specific survival; ORR, objective response rate; CTC, circulating tumor cells; mPFS, median progression-free survival; A, cohort A; B, cohort B; MMR, mismatch repair; ST, solid tumors; CR, complete response; pe, primary endpoint; mr-PFS, median radiographic-progression-free survival; anti-PD-1, anti-programmed cell death protein-1; anti-PD-L1, anti-programmed cell death protein-1 ligand; ICI, immune checkpoint inhibitor; MSI, microsatellite instability; Lu-PSMA, lutetium-prostate-specific membrane antigen; DRC, disease-control rate; ADC, antibody-drug conjugate; SD, stable disease; PR, partial response; OS, overall survival.