SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 288,300 new cases of Prostate cancer will be diagnosed in 2023 and 34,700 men will die of the disease.
The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPI), which include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.
DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1, BRCA2 and ATM genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Recently published data has shown that deleterious Germline and/or Somatic mutations in BRCA1, BRCA2, ATM, or other Homologous Recombination DNA-repair genes, are present in about 25% of patients with advanced prostate cancer, including metastatic CRPC. Approximately 12% of men with metastatic CRPC harbor a deleterious BRCA1 or BRCA2 mutation (BRCA1, 2%; BRCA2, 10%). Mutations in BRCA1 and BRCA2 also account for about 20-25% of hereditary breast cancers, about 5-10% of all breast cancers, and 15% of ovarian cancers.
The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.
RUBRACA® (Rucaparib) is an oral, small molecule inhibitor of PARP inhibitor, and in the Phase II TRITON2 study, Rucaparib showed a high level of activity in metastatic Castration Resistant Prostate Cancer (CRPC) associated with a deleterious BRCA alteration, in patients who had received previous treatment with a second-generation Androgen-Receptor Pathway Inhibitor (ARPI) and taxane-based chemotherapy.
TRITON3 is an open-label, controlled, randomized, Phase III trial, conducted to evaluate the benefit of Rucaparib in men with metastatic CRPC at an earlier stage of treatment, and to confirm and expand on data from the TRITON2 study. This study enrolled patients who had metastatic CRPC with a BRCA1, BRCA2, or ATM alteration, who had disease progression after treatment with a second-generation ARPI, and who had not received previous chemotherapy for metastatic CRPC. Patients were randomly assigned in a 2:1 ratio to receive Rucaparib 600 mg orally twice daily or a physician’s choice of therapy (Docetaxel or a second-generation ARPI such as Abiraterone acetate or Enzalutamide). Abiraterone acetate or Enzalutamide could not be selected if the patient had received either drug before trial initiation. Approximately 56% received Docetaxel in the control group. The median age was 70 years and baseline genomic, demographic, and disease characteristics were well balanced in the two groups although men of African descent were underrepresented relative to the general population. Among the patients who had undergone randomization, 302 patients had a BRCA alteration and 103 patients had an ATM alteration. In this study, there were smaller numbers of patients with BRCA1 alterations than with BRCA2 alterations. The Primary end point was the median duration of imaging-based Progression Free Survival (PFS) according to Independent Review. Secondary outcomes included Overall Survival (OS) and Objective Response Rate (ORR), Duration of Response, Time to progression according to Prostate Specific Antigen (PSA) testing and Patient-Reported Outcomes.
At 62 months, the median duration of imaging-based PFS was significantly longer in the Rucaparib group than in the control group, both in the BRCA subgroup (11.2 months and 6.4 months, respectively; HR=0.50) and in the intention-to-treat group (10.2 months and 6.4 months, respectively; HR=0.61; P<0.001 for both comparisons). These findings demonstrating the benefit of Rucaparib compared to the Docetaxel control group are significant, as numerous previous studies either did not include Docetaxel in the control group, or did not show the superiority of PARP inhibition to Docetaxel. These study findings were consistent with the results of previous studies, suggesting that repeated use of second-generation ARPIs appeared to have only modest activity and inferior to PARP inhibition. Among patients with measurable disease at baseline, the confirmed Objective Response in the Rucaparib group and the control group was 45% and 17% respectively in the BRCA subgroup, 35% and 16% respectively, in the intention-to-treat population and no response and 14% respectively in the ATM subgroup. Because there were a smaller number of patients with BRCA1 alterations than with BRCA2 alterations in this study, the treatment benefit was not conclusive in those with BRCA1 alterations.
In an exploratory analysis in the ATM subgroup, the median duration of imaging-based PFS was 8.1 months in the Rucaparib group and 6.8 months in the control group (HR=0.95), suggesting limited efficacy of Rucaparib in the ATM subgroup, similar to the results of previous clinical trials involving PARP inhibitors. The most frequent adverse events with Rucaparib were fatigue and nausea.
It was concluded that in patients with metastatic Castration-Resistant Prostate Cancer in whom treatment with an Androgen Receptor Pathway Inhibitor (ARPI) had failed, the use of Rucaparib resulted in a longer duration of imaging-based Progression Free Survival than a physician’s choice of Docetaxel or a second-generation ARPI.
Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. Fizazi K, Piulats JM, Reaume MN, et al., for the TRITON3 Investigators. N Engl J Med 2023; 388:719-732.
