Personalized precision combination therapies based on potential actionability and coalterations and therapeutic opportunities for CDK12-mutated prostate cancer.

Abstract

e17068 Background: Translational studies have reported that CDK12 aberrations in metastatic castration-resistant prostate cancer (mCRPC) are related to homologous recombination (HR) deficiency and focal tandem duplications(FTDs), characterized by gene fusions and fusion-induced neoantigens (FINAs). In prostate cancer,CDK12 aberrations as a biomarker have been reported associated with poor prognosis, whether hormonal and taxane therapies as well as to PARP inhibitors. Herein, we aimed to molecularly, pathologically, and clinically characterize CDK12-aberrant mCRPC. Methods: Clinical data and molecular analyses are collected from the mCRPC patients treated in our center. Thirty-two patients with prostate cancer underwent soft tissue biopsy or sufficient ctDNA(Circulating Tumor DNA) for NGS and confirmed the CDK12 aberrations. Twenty-eight patients had advanced to the stage of mCRPC, and twenty-seven of them had exhausted standard treatment.All of the twenty-seven patients consented to the individualized therapiees based on NGS.PSA50 response rate and progression-free survival(PFS) are used to describe clinical features and outcomes to various individualized therapies, including sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) and PD-1/PD-L1 inhibitors monotherapy or combined with other off-label drugs. Results: Of the 32 patients with CDK12-aberrant prostate cancer, 19(59.4%) had detected biallelic CDK12 alterations. At diagnosis,17 (68%) patients' PSA≥100ng (only 26 patients retained the PSA data), 27 (93.1%) had Gleason grade group 4-5(only 29 patients retained the pathology),16(51.6%) had lymph node metastasis, 16(51.6%) had bone metastasis.13 patients received PARPi combine NHT(Novel hormone therapy) or not after NHT therapy resistance,only 1 patient PSA response reached PSA50.9 patients received PARPi combine temozolomide,2 reached PSA50,1 patient's liver metastases were significantly reduced ang reached PR.In that five patients,4 of 5 were monotherapied by PARPi.21 patients accepted PD-1/PD-L1 combined with PARPi or other off-label drugs based on the NGS or not.Four patients accepted immune monotherapy,only 1 reached PSA50. In the remaining 17 combined treatment patients, PSA50 responses were noted in 23.5%. What is noteworthy is that,4 of 16 happened HPD(hyperprogressive disease) with clinical manifestations such as rapid increase of PSA and significant decrease of ECOG score. Conclusions: CDK12-aberrant mCRPC is an aggressive subtype and have worse prognosis to PARPi. PARPi combine with temozolomide may be a effective therapeutic schedule. Along with NGS development,more therapeutic drugs are available to us to benefits for patients.But immunotherapy is questionable to CDK12-aberrant mCRPC because of the lower response rate and higher risk of HPD.