ASCO GU 2021: Association of Co-Occurring Gene Alterations and Clinical Activity of Rucaparib in Patients with BRCA1 or BRCA2 Mutated (BRCA+) Metastatic Castration-Resistant Prostate Cancer (mCRPC)

( The TRITON2 study led to the approval of the PARP inhibitor rucaparib in patients with BRCA-mutated mCRPC that has progressed on prior androgen receptor signaling inhibition and one taxane chemotherapy. While response rates to rucaparib in different subgroups (germline vs. somatic, type of alteration) were similar, it is unknown how other co-occurring mutations, especially those that confer poor prognoses like TP53, PTEN, or RB1, impact the efficacy of rucaparib.

In this poster, Dr. Wassim Abida and colleagues utilized tumor or cell-free DNA analysis of genomic alterations to study the overall and PSA response rates in patients with various poor prognosis alterations in addition to BRCA alterations. In total, of the 115 patients with BRCA alterations studied, 42 patients were found to have TP53 mutations, 39 patients had alterations in PTEN, and 14 patients had alterations in RB1. The authors note that patients with mutated TP53 tended to have a shorter time from time to diagnosis to enrollment on the study and higher rates of visceral metastases, though they also tended to have lower Gleason scores. Patients with RB1 mutation had a higher incidence of visceral metastases, especially hepatic lesions.

When comparing PSA and radiographic response to detected genomic alterations, it is evident that patients with co-occurring mutations in TP53, PTEN, or RB1 have varying clinical responses across the spectrum from progressive disease to response. Indeed, as shown in the forest plots below, patients with BRCA-mutated CRPC and co-occurring mutations in these three genes had similar objective and PSA response rates as those without co-occurring mutations. There were too few RB1 alterations to draw a definitive conclusion about the lower ORR in RB1 mutated patients.


In summary, Dr. Abida concluded that although TP53, PTEN, or RB1 alterations are associated with poor prognosis in advanced prostate cancer, results from TRITON2 showed similar antitumor activity regardless of the co-occurrence of alterations in these genes. The low frequency of RB1 loss limited their conclusions for these specific genes and should be evaluated further in future studies.

Presented by: Wassim Abida, MD, PhD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Written by: Alok Tewari, MD, Ph.D., Medical Oncologist at the Dana-Farber Cancer Institute, during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021