Patients were considered to be short-lived when developed to mCRPC, despite significant progress in systemic and anti-androgen therapy. In this case, a mHSPC patient received multiple lines of therapy, and an acceptable clinical response to Olaparib and abiraterone-prednisone combination therapy was achieved. Genetic testing of ctDNA indicated a complicated mechanism for his final disease progression.
Previous studies reported the vital contribution of the alternative splice of AR-V7 to resistance to anti-androgen therapy[15, 16]. In our case, when developed to mCRPC, CTCs and AR-V7 mRNA testing were negative. This patient had a nearly one-year progression-free interval receiving abiraterone mono-therapy, basing on testosterone levels that remained castrated throughout the entire process. Disease progression was mainly due to a secondary AR-V7 overexpression as well as the epithelial-mesenchymal transition of prostate cells as in parallel with reported investigations. In addition, androgen receptor amplification or gain of function mutations of AR, as observed in ctDNA of this patient, would also continuously activate downstream AR signaling pathway overcoming extrinsic androgen inhibition[18, 19].
Recent progress delineated a subgroup of prostate patients, especially the loss of function mutations of BRCA2 gene, benefiting from the treatment of PARP inhibitors. In TOPARP-A and TOPARP-B study [6, 7], Olaparib mono-therapy has antitumor activity against mCPRC with HRR or DDR gene alterations. TOPARP-B study showed BRCA1/2 mutated mCRPC patients yielded an objective response rate of 83.3%. Recently released results from PROfound study showed that Olaparib provided a statistically significant and clinically meaningful improvement on BICR assessed rPFS, especially for BRCA2-mutated patients. A similar benefit was observed in TRITON2 (rucaparib)[20, 21] and GALAHAD (niraparib) study.
Neither germline BRCA2 nor BRCA1 deleterious mutation was found in this patient as shown by the first genetic testing. Supported by the conclusion from study 08, Olaparibin combination with abiraterone showed significant clinical benefit and this efficacy lasted for nearly five months. Progression was inevitably occurred, which led to the second time of genetic testing. Comprehensive genomic profiling uncovered that, instead of BRBA1/2, this patient had a germline PALB2 nonsense mutation which may lead to truncation of PALB2 protein. As this patient was resistant to prior abiraterone treatment together with AR amplification and AR-V7 overexpression, abiraterone may not be able to block AR signaling triggering “BRCAness”. PALB2, as one of tumor suppressor genes, by physically interacting with BRCA2 followed by recruiting RAD51 to DNA breaks, plays critical roles in repairing DNA double-strand breaks by homologous recombination (HR). A couple of studies indicated PALB2 deleterious mutations were associated with clinical benefit from PARP inhibitors[6, 20]. For instance, TOPARP-B study showed patients with PALB2 germline or somatic loss of function mutation may benefit from Olapraib treatment.
This patient had disease worsened after five months’ disease relieving period, which indicated PARP inhibitor resistance. The most known mechanism is the secondary somatic reverse mutation in germline mutated genes. Goodall et al reported in a mCRPC patient with germline PALB2 p.L253Ifs*2, who had a 9-month clinical benefit from Olaparib and two reverse somatic mutations in PALB2 were detected in his ctDNA at disease progression. In our case, this patient had a germline PALB2 p.Q251* nonsense mutation. Two somatic reverse mutations which may restore PALB2 reading frame were observed when the disease progressed.
Besides reverse mutation as a potential mechanism on PARP inhibitor resistance, EwaGogola et al concluded four major mechanisms of PARP inhibitor resistance including upregulation of drug efflux, restoration of homologous recombination, target-specific resistance to PARP inhibitor and restoration of stalled replication fork protection. Meanwhile, by the genomic profiling, we proposed restoration of homologous recombination was not only induced by reverse mutations of PALB2. Loss of function mutation of PTEN together with FGFR1 amplification may directly and indirectly activated PI3K-AKT-mTOR as well as RAS-RAF-MAPK/ERK signaling pathway. Activation of these oncogenic pathways may further drive the expression of HR genes compensating DNA double breaks. In addition, activation of these signaling pathway may accelerate cell-cycle and evade apoptosis. In this case, the mechanism of PARP inhibitor resistance was explored in detail via comprehensive genomic profiling. Further validation at the functional level is warranted.
Several therapeutic issues need to be concerned. Firstly, as fully respecting patient’s willingness, comprehensive genomic profiling can only be performed when the resistance of Olaparib occurred. In this circumstance, it could not distinguish the primary or secondary source of these two somatic PALB2 mutations. Secondly, therapeutically, instant multiple gene testing is definitely essential. Detection of germline PALB2 aberration at a relatively early stage may make this patient receive Olaparib mono-therapy, but not being enrolled into the Proxalutamide clinical trial. Thirdly, PALB2 is a cancer susceptibility gene that may be increasing the risk of breast cancer as well as be substantially associated with the onset of ovarian cancer, pancreatic cancer and male breast cancer. Concerning this patient carried a PALB2 germline pathogenic variation, his first and secondary degree relatives need to visit a genetic counselor for further evaluation.