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Published on: March 6, 2018
Rucaparib or Physician's Choice in Metastatic Prostate Cancer
Karim Fizazi1, Josep M Piulats1, M Neil Reaume1
1From Gustave Roussy Institute, Paris-Saclay University, Villejuif, France (K.F.); Institut Català d'Oncologia-Bellvitge Institute for Biomedical Research -CiberOnc, Barcelona (J.M.P.), and the Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria University Hospitals, IBIMA, Málaga (M.I.S.) - both in Spain; the Ottawa Hospital Research Institute, Ottawa (M.N.R.), CancerCare Manitoba, Winnipeg (J.R.G.), and Princess Margaret Cancer Centre (S.S.S.) and Odette Cancer Centre, Sunnybrook Health Sciences Centre (U.E.), Toronto - all in Canada; Mount Vernon Cancer Centre, Northwood (P.O.), Guy's Hospital (E.P.) and Guy's Hospital and Sarah Cannon Research Institute (S.C.), London, Velindre University NHS Trust, Cardiff (J.S.), and Clovis Oncology UK, Cambridge (C.A.H., S.P.W.) - all in the United Kingdom; St. Vincent's University Hospital and Cancer Trials Ireland, Dublin (R.M.), and Cork University Hospital, Wilton (R.M.B.) - both in Ireland; Herlev University Hospital, Herlev (H.L.), and Copenhagen University Hospital, Rigshospitalet, Copenhagen (G.D.) - both in Denmark; Urology Associates, Nashville (D.M.); European Institute of Oncology IRCCS, Milan (F.N.); Sharp HealthCare, San Diego, CA (C.R.); Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York (W.A.); Universitätsklinikum Köln, Cologne, Germany (A.H.); Medical University of Vienna, Vienna (A.H.); Genesis Care, North Shore, Sydney (L.K.); University Hospital of Liège, CHU Sart-Tilman, Liège, Belgium (B.S.); Clovis Oncology, Boulder, CO (A.L., D.D.); the University of Minnesota, Minneapolis (C.J.R.); and Mayo Clinic, Phoenix, AZ (A.H.B.).
Background:
In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study.
Methods:
In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1, BRCA2, or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review.
Results:
Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea.
Conclusions:
The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).
Insights
Rucaparib significantly improved progression-free survival in patients with metastatic castration-resistant prostate cancer and BRCA alterations. This PARP inhibitor offers a new treatment option for this patient population.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) with deleterious BRCA alterations presents a therapeutic challenge.
- Previous phase 2 studies indicated activity of rucaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in this setting.
- Further data were required to validate these preliminary findings.
Purpose of the Study:
- To evaluate the efficacy of rucaparib compared to standard treatments in patients with mCRPC harboring BRCA1, BRCA2, or ATM alterations.
- To assess the impact of rucaparib on imaging-based progression-free survival in this specific patient group.
Main Methods:
- A randomized, controlled, phase 3 trial (TRITON3) was conducted.
- Patients with mCRPC and a documented BRCA1, BRCA2, or ATM alteration, who progressed after second-generation androgen-receptor pathway inhibitor (ARPI) treatment, were enrolled.
- Participants were randomized 2:1 to receive oral rucaparib (600 mg twice daily) or physician's choice of docetaxel or a second-generation ARPI.
Main Results:
- The study included 270 patients receiving rucaparib and 135 in the control arm (intention-to-treat).
- In the BRCA-altered subgroup, median imaging-based progression-free survival was 11.2 months with rucaparib versus 6.4 months with control (HR, 0.50; 95% CI, 0.36 to 0.69).
- Rucaparib demonstrated a significant improvement in progression-free survival in both the BRCA subgroup and the overall intention-to-treat population.
Conclusions:
- Rucaparib significantly prolonged imaging-based progression-free survival compared to control medication in patients with mCRPC and BRCA alterations.
- Rucaparib represents a promising therapeutic option for patients with mCRPC and specific genetic alterations.
- Fatigue and nausea were the most common adverse events associated with rucaparib treatment.
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