Tweet Chat Recap: Sequencing Strategies for a Post-Docetaxel Patient with Metastatic Castration-Resistant Prostate Cancer
May 21, 2020 05:30pm
By Danielle Ternyila
"Rucaparib’s approval could have a profound impact on patients with BRCA2 and BRCA1 mutations, who have no other targeted treatment option available to them based on this mutation."
The FDA has approved rucaparib (Rubraca) the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy.1
“[Rucaparib’s] approval could have a profound impact on patients with BRCA2 and BRCA1 mutations, who have no other targeted treatment option available to them based on this mutation,” Charles J. Ryan, MD, the B.J. Kennedy Chair in Clinical Medical Oncology and the director of the Division of Hematology, Oncology, and Transplantation, University of Minnesota, told Targeted Oncology. “The approval further supports genomic testing in all patients with metastatic prostate cancer, in particular CRPC, to determine if they are eligible to receive PARP inhibitor therapy.”
Continued approval for rucaparib in this indication is contingent upon verification of clinical benefit in confirmatory trials.
Data supporting the approval came from the TRITON trials that explored the use of PARP inhibition with rucaparib in patients with mCRPC and alterations in homologous recombination repair (HRR)–related genes.
In the phase II TRITON2 trial, patients with mCRPC and a BRCA1/2 mutation had an objective response rate (ORR) of 43.9% by RECIST/Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria; the ORR by independent radiological review was 40.4%. Sixty percent of radiographic responses lasted at least 24 weeks. The prostate-specific antigen (PSA) response rate (≥50% decrease) was 52.0%.2
The international, multicenter, open-label phase II study enrolled 85 men with mCRPC and screened them for the presence of deleterious germline or somatic alterations in 13 HRR genes. Patients had progressed on androgen receptor (AR)–directed therapy and a prior taxane-based chemotherapy regimen for castrate-resistant disease.
Treatment of 600 mg rucaparib was administered twice daily until radiographic progression or discontinuation. The primary end points were ORR by RECIST/PCWG3 criteria and PSA response rate.
The most common treatment-emergent adverse events reported with rucaparib in the TRITON2 trial were asthenia/fatigue, nausea, anemia/decreased hemoglobin, decreased appetite, increased aspartate aminotransferase and alanine aminotransferase, constipation, vomiting, and diarrhea.
TRITON3 is an ongoing multicenter, randomized, open-label phase III trial of rucaparib in comparison with physician’s choice of therapy in patients with mCRPC associated with a homologous recombination gene deficiency (NCT02975934). The study will serve as confirmation of the benefit seen in the TRITON2 trial.
All patients had progressed on prior AR-directed therapy in the mCRPC setting. Patients were randomized 2:1 to either rucaparib 600 mg twice daily or physician’s choice of therapy. Physician’s choice of treatment consisted of abiraterone acetate (Zytiga), enzalutamide (Xtandi), or docetaxel. Crossover was allowed to the investigational arm at confirmed radiographic progression.
The primary end point is radiographic progression-free survival by RECIST/PCWG3 criteria, and secondary end points include ORR, duration of response, patient-reported outcomes, overall survival, and safety.
“The role of rucaparib in the chemotherapy-naïve CRPC population continues to be studied in the TRITON3 randomized trial, and further expansion of the role of rucaparib in the disease may be considered following the completion of that larger study. Additionally, further work continues to define the role of PARP inhibitors in the setting of non–BRCA-associated DNA repair defects,” Ryan added.
The label for rucaparib includes warnings for myelodysplastic syndrome, acute myeloid leukemia, and embryo-fetal toxicity.
1. Rubraca® (Rucaparib) approved in the u.s. as monotherapy treatment for patients with brca1/2-mutant, metastatic castration-resistant prostate cancer (mcrpc) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy [news release]. Boulder, Colorado: Clovis Oncology; May 15, 2020. https://bit.ly/3cC3SS0. Accessed May 15, 2020.
2. Abida W, Campbell D, Patnaik A, et al. Preliminary results from the TRITON2 study of rucaparib in patients (pts) with dna damage repair (DDR)-deficient metastatic castration-resistant prostate cancer (mCRPC): updated analyses. Ann Oncol. 2019;30(suppl 5):v325-v355. doi: 10.1093/annonc/mdz248.