Two Phase II studies of rucaparib in BRCA mutant ovarian cancer- Clovis Oncology

Clovis Oncology announced updated Phase II results from two ongoing clinical studies with rucaparib: ARIEL-2 (a registrational study) and Study 10. Data from the ARIEL 2 study of 204 patients show compelling clinical activity, including the first presentation of PFS (progression free survival) for each subgroup followed in the study. A median PFS of 9.4 months in BRCA-mutant patients and a median of 7.1 months in patients with a BRCA-like signature were observed, compared to biomarker negative patients, in which median PFS was 3.7 months. The most robust clinical responses were observed in patients with tumor BRCA mutations: 82 percent (32/39) of BRCA-mutant patients achieved a RECIST and/or CA-125 response and 69 percent (27/39) achieved a RECIST response. Responses were observed in both germline and somatic BRCA-mutant tumors. Four CRs (complete responses) were observed in the somatic BRCA-mutant group. A 94 percent DCR (disease control rate) (CR, PR or SD > 24 weeks) was also observed. Responses were durable with 18 of 27 responders still ongoing at time of analysis.

These patients had received a median of two prior therapies with a range of one to five prior therapies. Importantly, results from ARIEL 2 demonstrate that tumor HRD analysis can identify a broader range of patients who may benefit from rucaparib therapy. Forty-five percent (33/74) of patients with the pre-specified BRCA-like signature achieved a RECIST and/or CA-125 response, and 30 percent (22/74) achieved a RECIST response. Responses were durable with 17 of 22 responders still ongoing at time of analysis. A 73 percent DCR was also observed. As expected, activity was limited in biomarker negative patients. A 39 percent DCR was also observed.

ARIEL 2 data presented demonstrate that rucaparib is well tolerated with a manageable safety profile. The most common treatment-related AEs reported in up to 15 percent of all patients included nausea, asthenia/fatigue and transient ALT/AST elevations. These events were mostly Grade 1/2.

Study 10 Data in Platinum-Sensitive Germline BRCA-mutant Patients- Data from a second Phase II study of rucaparib in ovarian cancer were presented in a poster presentation and poster discussion session.The Phase II portion of Study 10, the initial dose finding study of rucaparib, was expanded to enroll 41 patients with relapsed, high-grade platinum-sensitive ovarian cancer associated with a deleterious germline BRCA mutation. These patients had all received 2-4 prior treatment regimens, and had a progression-free interval of six months or greater after their most recent platinum regimen. Patients were treated with the recommended Phase II dose of 600mg BID.Consistent with the ARIEL 2 data in BRCA-mutant patients, a robust ORR (overall response rate) was observed in this patient population. In 35 patients evaluable for activity, 74 percent (26/35) of patients achieved a RECIST and/or CA-125 response, and 66 percent (23/35) achieved a RECIST response; a 77 percent disease control rate (DCR) was observed. Robust activity was observed regardless of type of BRCA mutation, length of progression-free interval between platinum therapies and number of prior treatments: response rates (RECIST and CA-125) ranged from 72 to 80 percent in those categories, or 61 to 78 percent for RECIST alone. Responses to rucaparib were durable: 15 of 23 responses were still ongoing at time of analysis with a median duration of response of over 11 months. Importantly, 77 percent of patients treated with at least 3 lines of chemotherapy achieved a RECIST and/or CA-125 response, and 69 percent achieved a RECIST response. This is the subject population of the ongoing ARIEL 2 Extension registration study. Rucaparib was well tolerated with a manageable safety profile; the most common AEs were fatigue/asthenia, nausea and anemia. Any Grade 3/4 AEs were successfully managed with dose modification. No patients discontinued due to treatment-related adverse events.

Comment:The drug would be in direct competition to AstraZeneca's already-approved Lynparza (olaparib), which gained the FDA approval in December 2014 as a monotherapy in patients with deleterious or suspected deleterious gBRCAm advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.