Identifying mutations in the DNA Damage Repair (DDR) genes BRCA 1 & 2, ATM, PALB2 and CHEK2 carries clinical significance and opportunities. These genes (and several others) cooperate in repairing single-and double-strand DNA breaks, that if not corrected, impair the fidelity of genome duplication in cell division. These occasionally result in pathologic mutations. When functional, these DDR genes serve as the first line of defense to correct pathological mutations. When the BRCA-like genes are mutated and nonfunctional for DNA repair, the repair falls upon the PARP family of enzymes (Poly (ADP-ribose) polymerase), the second line of defense. However, it is undesirable to preserve the function of the pathologic mutations. The prevention of PARP repair is accomplished by the family of FDA approved PARP inhibitors (olaparib, rucaparib, niraparib and talazoparib) which deactivate PARP. When both first- and second-line repair systems are inactivated, the cells accumulate DNA damage and die.
Incidence of Significant Mutations in DDR Genes:
“Inherited DNA-Repair Germline Mutations in Men with Metastatic Prostate Cancer” (Nelson et al., NEJM. 2016) reported that 11.8 % of men had deleterious germline mutations disrupting DNA repair. These confer greater cancer aggressiveness. The genes most affected were BRCA2, 5.3%; ATM, 1.6%; CHEK2, 1.9% and PALB2, 0.4%. The incidence of these adverse mutations increases in men with higher Gleason scores to ~20% at Gleason >8 and above. Mutations in men with newly diagnosed metastatic PC occurred in 20 – 25% (with ~ 10 – 15% having BRCA 1/2) suggesting that mutations are induced as treatments proceed. This high incidence underscores the importance of early genomic testing to unveil treatment options. Current NCCN guidelines suggest screening for DDR mutations in men diagnosed with high-risk disease, regional nodal spread and metastatic disease to guide family counseling and consideration of using PARP inhibitors.
How Are Germline and Somatic Mutations Diagnosed?
At diagnosis, inherited (germline) mutations and mutations that arise as the cancer evolves within the prostate are assessed by submitting biopsy tissue or the prostate specimen for pathologic evaluation. Diagnosing the mutations that developed during treatment (somatic mutations) requires a different approach since somatic mutations are heterogeneous at different metastatic sites. A biopsy of a single metastasis may miss a treatable mutation occurring at another metastasis. However, each metastatic site contributes its unique mutations into blood, allowing diagnosis of the full spectrum of mutations by submitting blood. Specialty labs assess these mutations in circulating tumor cells: CellSearch, Univ.of Washington, FoundationOne Medicine, Gardant360, etc.). The blood assay can be repeated as treatment proceeds for updated information.
How to Incorporated PARP inhibitors in Cancer Management? — Two Options Based on Clinical Trials
1) Guidance from the PROfound Trial: olaparib was FDA approved in 2020 for treatment of men with advanced mCRPC harboring mutations in BRCA 1,2 and ATM. (BioSpace. 2019). Olaparib alone was compared to either Zytiga or Xtandi after progression on either of those two agents (i.e., 2nd-line). The median Radiographic Progression-Free Survival (rPFS) for olaparib was 7.4 months vs 3.6 for the control group. In final analysis of Overall Survival olaparib was 18.5 months vs 15.1 for control. The significant adverse effects (grade 3 or better) for olaparib were anemia 20%, nausea 41%, fatigue 3%, decreased appetite 30%; and diarrhea 21%.
2) The PROpel Trial moved olaparib up to 1st-line for men with mCRPC and compared olaparib+Zytiga+prednison vs Zytiga+prednisone in 796 men with and without mutations in DDR genes. (Lancet Oncology, 2023): median rPFS (radiographic Progression-Free Survival) for the combination was 24.8 months vs 16.6 months for Zytiga/prednisone. The overall survival analysis was 42.1 months for the combination vs 34.7months for Zytiga/prednisone. The trial showed benefit for men lacking HRR-mutations but less so.
3) The FDA has approved the PARP inhibitors: olaparib (PROfound Trial and PROpel Trials), rucaparib (Triton Trials) talazoparib (TALAPRO) and niraparib (GALAHAD & AMPLITUDE). Since 2023 the PARP inhibitors have frequently been combined with Zytiga or Xtandi because together they more effectively inhibit the androgen receptor’s role in repair of DNA breaks and increase PARP dependency. No head-to-head comparison trials have been conducted. The TALAPRO -2 Trial found talazoparib/Xtandi effective: rPFS 27.9 months vs 16.4 months for Xtandi alone.
The Future View of PARP inhibitors:
The PARP inhibitors are moving forward in the treatment cycle to treat mHSPC (metastatic Hormone-Sensitive Prostate Cancer) and biochemical recurrence. Triple drug strategies include PARP inhibitors combined with ARPIs ( i.e., Zytiga and Xtandi) along with immunotherapy, radioligand therapy and ATR inhibitors (Ceralasertib, a regulator of DNA damage repair).
The LuPARP Trial is early phase and combines Pluvicto (177-Lutetium) and olaparib in men with mCRPC harboring mutations in DNA damage repair genes. The rationale is that Pluvicto creates double stranded DNA breaks and olaparib blocks their repair.
BOTTOM LINE:
The implementation of PARP inhibitors in such a wide range of clinical applications offers men strong encouragement that new treatments are becoming available to control metastatic prostate cancer.