- Ovarian and breast cancer patients harboring germline BRAC1/2 mutations are treated
with PARP inhibitors. BRCA1 and BRCA2 are pivotal in the homologous
recombination (HR) pathway.
- Research evaluating the efficacy of PARP inhibitors in metastatic castration-resistant
prostate cancer (mCRPC), has shown favorable clinical activity. Based on these
encouraging results, olaparib and recaparib have received FDA approval in mCRPCs.
- However, reversion mutations, restoring the BRCA function confers resistance to
platinum-based chemotherapy and PARP inhibitors.
- The case report represents a 58-year-old male with mCRPC and a germline BRCA2
mutation. The tests revealed a Gleason’s 5 + 5 prostate adenocarcinoma.
- The patient had a history of moderate aortic stenosis, left ventricular hypertrophy, left
atrial dilatation, diabetes, hypercholesterolemia, and vitiligo at the time of diagnosis.
- After luteinizing hormone-releasing hormone agonists with bicalutamide, he received
the first cycle of docetaxel chemotherapy. However, the treatment was discontinued
due to disease progression.
- Thereafter, he was treated with enzalutamide, resulting in a reduced pain score, PSA,
and ALP. The treatment was terminated after an increase in the PSA and ALP.
- He later received 6 cycles of second-line cabazitaxel chemotherapy until clinical and
biochemical progression. He received third-line carboplatin chemotherapy based on
his family history and aggressive disease. However, the treatment was discontinued
after 6 cycles owing to the disease progression. The patient was treated with rucaparib
600 mg twice daily (BID) in the aftermath of a deleterious BRCA2 c.5727_5728insG
(N1910fs*2) mutation in the original tumor biopsy.
- The patient was also detected with a CDKN2A P114L mutation after carboplatin
- Besides, the BRCA2 germline mutation, NGS detected 12 more reversion mutations.
Six of these mutations, close to the original mutation, restored the BRCA2 open
reading frame (ORF). Four of the 12 mutations caused loss of BRCA repeat
sequences BRC5- BRC8. The last mutation covered the nucleotides 5333–6841 of the
coding region and the first 197 nucleotides of the intron.
- Despite rucaparib treatment, the patient suffered from sepsis, uncontrolled back pain,
and disease progression. This forced discontinuation of rucaparib permanently.
- The presence of reversion mutations indicated a different genomic or biological
context inducing secondary mutations.
- The region of BRC5-BRC8 stabilizes the RAD51 filament in the HR pathway. The
large deletion in this region may induce resistance to mitomycin C. While, it is
difficult to predict whether these changes were polyclonal or multiple reversion
alterations in a one-tumor cell, the stable PSA levels indicate that not all tumor clones
had the mutations.
- It is likely that the CDKN2A P114L mutation-induced resistance to enzalutamide.
However, the origin of the mutation remains unknown. RB1 loss and CCDN1
amplification along with the cell-cycle upregulation in patients treated with
enzalutamide suggest the importance of cell-cycle kinases in the development of
- Although rucaparib exhibits decent clinical activity in mCRPC patients, it is important
to understand how to use the PARP inhibitors and platinum-based chemotherapies to
achieve maximum efficacy.