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35820411000001101

New Medicines

RubracaOvarian cancer - first line maintenance in newly diagnosed patients in response to chemotherapy - monotherapy

Information

Rubraca
Licence extension / variation
Clovis Oncology
Clovis Oncology

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Pre-registration (Filed)
Sep 22Clovis files applications with the EMA and FDA for approval of a new indication for rucaparib as first-line maintenance treatment for women with advanced ovarian cancer regardless of biomarker status who have responded to first-line platinum-based chemotherapy. The submissions are based on the positive data from the monotherapy analysis of the PIII ATHENA trial (ATHENA-MONO) [6].
May 22FDA has asked for additional data, advising Clovis that it should not file for approval until the Athena-Mono trial has accrued at least 50% pre-specified death events for an overall survival analysis. The study is currently only halfway there, with overall survival findings about 25% mature. Clovis has announced that it needs to raise additional money to keep the business afloat [4].
Mar 22Data from the ATHENA-MONO trial have been submitted for presentation at the American Society of Clinical Oncology Annual Meeting in Jun 2022. Clovis also intends to provide these data to US and European regulatory authorities and is on track to submit filings during Q2 and Q3 2022, respectively, in those geographies [3].

Category

Poly(ADP-ribose) polymerase (PARP) inhibitor
There are around 7,400 new ovarian cancer cases in the UK every year. Almost 6 in 10 ovarian cancer cases are diagnosed at a late stage. Incidence rates for ovarian cancer have been projected to rise by 15% in the UK between 2014 and 2035, to 32 cases per 100,000 females by 2035 [1].
Ovarian cancer - first line maintenance in newly diagnosed patients in response to chemotherapy - monotherapy
Oral

Further information

Yes

Trial or other data

Jun 22PIII ATHENA RCT (n=538) found, after response to first line chemotherapy, maintenance rucaparib provided a superior progression free survival vs placebo (20.2 vs 9.2 months, HR 0.52, 95%CI 0.40-0.68). It was superior in both homologous recombination deficiency +ve & -ve subpopulations [5].
Mar 22Clovis Oncology announce positive top-line data from the monotherapy arm of the ATHENA trial (ATHENA-MONO) demonstrating that rucaparib as maintenance treatment successfully achieved the primary endpoint of significantly improved investigator-assessed PFS vs placebo. In the HRD-positive patient population, the rucaparib arm (n=185) successfully achieved statistical significance over the placebo arm (n=49) for the primary endpoint of PFS with a hazard ratio of 0.47 (95% CI: 0.31-0.72). The median PFS for the HRD-positive patient population treated with rucaparib was 28.7 months vs 11.3 months among those who received placebo (p=0.0004). In all patients studied (ITT or all comers; n=538) rucaparib also showed statistical significance with the rucaparib arm (n=427) successfully achieving statistical significance vs placebo arm (n=111) for PFS with a hazard ratio of 0.52 (95% CI: 0.40-0.68). The median PFS for all patients enrolled in ATHENA-MONO and treated with rucaparib was 20.2 months vs 9.2 months among those who received placebo (p<0.0001). The safety of rucaparib observed in ATHENA-MONO was consistent with both the current US and European labels [3].
Nov 21PIII ATHENA trial is active but no longer recruiting. Collection of PFS data is due to complete Dec 24 [2].
May 18PIII ATHENA trial to evaluate the efficacy of rucaparib and nivolumab as maintenance treatment following response to front-line treatment in newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer starts (NCT03522246). Evaluation of the progression-free survival is the defined primary endpoint of the trial. The randomised, double-blind, placebo-controlled trial will enrol 1,000 adults, including in the US and Europe (plus UK). Patients will be randomised to one of 4 arms; oral rucaparib plus IV nivolumab, oral rucaparib plus IV placebo, oral placebo plus IV nivolumab, and oral placebo plus IV placebo. Evaluation of the progression-free survival is the defined primary endpoint of the trial [2].

Evidence based evaluations

Rubraca Metastatic castration resistant prostate cancer with a deleterious BRCA mutation - monotherapy

Information

Rubraca
Licence extension / variation
Clovis Oncology
Clovis Oncology

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Launched
Oct 22Clovis plans to file an application in the US for full approval in the BRCA subgroup in Q1 2023 but intends to discuss with the FDA about the broader population because of a lack of showing in the ATM subgroup in the TRITON 3 trial [11].
May 20Approved in US 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 [8].
Jan 20FDA grants priority review to sNDA for rucaparib as monotherapy treatment for patients with BRCA1/2-mutant recurrent, metastatic castrate-resistant prostate cancer, based on data from TRITON clinical program [7].
Oct 18Granted Breakthrough therapy status in the US based on initial efficacy and safety results from the ongoing PII trial, TRITON 2 (NCT02952534). Initial data from this study will be presented for the first time at the 2018 European Society for Medical Oncology (ESMO) Congress later this month [1]

Category

Poly(ADP-ribose) polymerase (PARP) inhibitor
Approx 345,000 men in Europe were diagnosed with prostate cancer in 2012 and estimates indicate >164,000 men in the US will be diagnosed with prostate cancer in 2018. Castration-resistant prostate cancer has a high likelihood of developing metastases. Metastatic castration-resistant prostate cancer (mCRPC), is an incurable disease, usually associated with poor prognosis. Approximately 12% of mCRPC patients have a deleterious mutation in BRCA1 or BRCA2 [1].
Metastatic castration resistant prostate cancer with a deleterious BRCA mutation - monotherapy
Oral

Further information

Yes

Trial or other data

Oct 22In the PIII TRITON 3 study, rucarparib reduced the risk of tumour progression or death by 39% versus chemotherapy or second-line androgen deprivation therapy in patients with metastatic castration-resistant prostate cancer (mCRPC) with mutations in BRCA or ATM. The trial serves as the confirmatory study for the FDA accelerated approval of Rubraca for BRCA-mutated mCRPC in patients who have received an androgen receptor blocker and a taxane-based chemotherapy. Now, Clovis hopes to convert that approval, granted in 2020, into a full approval and expand Rubraca to mCRPC patients who have not received chemotherapy. In TRITON3, the rucaparib benefit in slowing disease progression appeared to be primarily driven by the BRCA-mutated group. There, the drug significantly cut the risk of progression or death by 50%. Patients on rucaparib lived a median 11.2 months, versus 6.4 months in the control group, which received physicia choice of treatment including the chemotherapy docetaxel or a next-generation androgen receptor-targeted therapy of either Zytiga or Xtandi. In an exploratory analysis in the ATM group, the drug showed almost no risk reduction. Patients in the rucaparib arm went 8.1 months without progression, versus 6.8 months in the control group. Mature data on patient survival actually favoured the control arm among the ATM patients. Overall survival in the BRCA subgroup was not mature but favoured rucaparib at the interim analysis [11].
Jul 21Recruitment continues in PIII TRITON 3 [10].
Dec 20PIII TRITON 3 study continues to recruit [9].
Dec 19PIII TRITON 3 study is recruiting; timescales unchanged [6].
Nov 18PIII TRITON 3 study is recruiting (NCT02975934) [5].
Oct 18Results of TRITON 2 reported at the annual European Society for Medical Oncology (ESMO) meeting, where the company highlighted results showing that rucaparib provoked responses in 44% of patients with BRCA 1/2 mutated tumours. It also significantly decreased the levels of prostate-specific antigen (PSA) in 51% of evaluable patients with BRCA 1/2 alterations [3]. 25/12/2018 08:58:54
Jan 17PIII multicentre, randomised, open label trial (NCT02975934; TRITON3) commenced to investigate efficacy of rucaparib vs physician´s choice of therapy for patients with metastatic castration resistant prostate cancer associated with homologous recombination deficiency. Enrolment is planned for approx 400 patients. The primary end point is defined as the radiologic progression-free survival, confirmed by independent radiology review (IRR). Estimated primary completion end date is Feb 2022 [2].
Nov 16PII TRITON 2 trial in patients with metastatic castration resistant prostate cancer starts (CO-338-052; NCT02952534). The trial will evaluate the safety and efficacy of oral rucaparib in patients with metastatic castration-resistant prostate cancer, including patients with BRCA mutations and ATM mutations (both inclusive of germline and somatic) or other deleterious mutations in other homologous recombination (HR) repair genes. The primary end points of the trial are radiologic overall response rate in patients with measurable disease and PSA response rate in patients who do not have measurable disease. The open-label trial is enrolling approximately 160 patients in the US, Australia, Belgium, Canada, Denmark, France, Germany, Ireland, Israel, Italy, the UK [4].

RubracaOvarian cancer - first line maintenance in newly diagnosed patients in response to chemotherapy - with nivolumab

Information

Rubraca
Licence extension / variation
Clovis Oncology
Clovis Oncology

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

Poly(ADP-ribose) polymerase (PARP) inhibitor
There are around 7,400 new ovarian cancer cases in the UK every year. Almost 6 in 10 ovarian cancer cases are diagnosed at a late stage. Incidence rates for ovarian cancer have been projected to rise by 15% in the UK between 2014 and 2035, to 32 cases per 100,000 females by 2035 [1].
Ovarian cancer - first line maintenance in newly diagnosed patients in response to chemotherapy - with nivolumab
Bladder instillation