Barcelona, Spain (UroToday.com) Rucaparib is a PARP inhibitor and has shown antitumor activity in patients with mCRPC and a deleterious DNA damage repair-deficient gene alteration. Initial results from the phase II TRITON2 study evaluating rucaparib in men who have progressed on an androgen receptor directed therapy and chemotherapy demonstrated confirmed radiographic and PSA responses in 44.0% and 51.1% of patients with a deleterious BRCA1/2 alteration, initially presented at ESMO 2018
Based on this data, the US FDA granted breakthrough therapy designation for rucaparib as a monotherapy of patients with BRCA1/2-mutated mCRPC who have received >=1 prior androgen receptor directed therapy and a taxane based chemotherapy. At the ESMO 2019 prostate cancer session Dr. Wassim Abida and colleagues presented an updated analysis of TRITON2.
TRITON2 is an ongoing phase 2 study evaluating rucaparib 600 mg BID in patients with mCRPC and a deleterious germline or somatic alteration in BRCA1, BRCA2, ATM, CDK12, or other prespecified DDR gene. Eligible patients have progressed on 1–2 lines of androgen receptor–directed therapy and 1 line of taxane-based chemotherapy for mCRPC.
As of February 28, 2019, 190 patients had received rucaparib with a median follow-up of 13.1 months (range 4.1-28.5 months): 98 with a BRCA1/2 alteration, 57 with an ATM alteration, 14 with a CDK12 alteration, 7 with a CHEK2 alteration, and 14 with another DDR gene alteration. Among the patients with a BRCA mutation and measurable disease at baseline, 43.9% had a confirmed ORR, and responses were durable with the majority lasting >24 weeks.
ORR was poor for the other patients: 9.5% for ATM, and 0% for both CDK12 and CHEK2. Among patients with BRCA mutations, 52.0% had a confirmed PSA response (>50% decrease), with a median duration of PSA response of 5.5 months.
Among other patients, PSA response was poor: 3.5% for ATM, 7.1% for CDK12, and 14.3% for CHEK2. With regards to safety, 56.3% had at least one treatment related adverse event grade 3-4, most commonly anemia (17.9% grade 3-4) and fatigue (10.5% grade 3-4).
The TRITON2 study concluded with several concluding statements:
- Consistent with prior reports, rucaparib demonstrates promising efficacy in patients with mCRPC and a germline or somatic BRCA or other DDR gene alteration à 43.9% had an objective response, and 52% had a confirmed PSA response
- No objective responses have been observed in patients with an ATM or CDK12 alteration
- The safety profile of rucaparib is consistent with prior reports in ovarian and prostate cancer
- In addition to the ongoing enrollment to TRITON2, the randomized, phase III TRITON3 study is evaluating rucaparib vs physician’s choice of second-line AR-directed therapy or docetaxel in chemotherapy-naïve patients with mCRPC and alterations in BRCA1/2 or ATM who progressed on one prior AR-directed therapy.
Presented by: Wassim Abida, MD, PhD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, New York, USACo-authors: D. Campbell,2 A. Patnaik,3 B. Sautois,4 J. Shapiro,5 N. Vogelzang,6 A. Bryce,7 R. Mcdermott,8 F. Ricci,9 J. Rowe,10 J. Zhang,11 A. Simmons,12 D. Despain,12 M. Dowson,13 T. Golsorkhi,12 S. Chowdhury14
2. University Hospital Geelong, Geelong, AU
3. The University of Chicago, Chicago, US
4. Centre Hospitalier Universitaire Sart Tilman, Liège, BE
5. Cabrini Health, Malvern, AU
6. US Oncology Research c/o Comprehensive Cancer Crts of NV, Las Vegas, US
7. Mayo Clinic, Phoenix, US
8. Adelaide and Meath Hospital (Incorporating the National Children's Hospital), Dublin, IE
9. Institut Curie, Paris, FR
10. The University of Texas Health Science Center at Houston and Memorial Hermann Cancer Center, Houston, US
11. Moffit Cancer Center, Tampa, US
12. Clovis Oncology, Inc., Boulder, US
13. Clovis Oncology UK Ltd., Cambridge, UK
14. Guy's and St. Thomas' Hospital NHS Trust, London, UK
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain