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Clovis Oncology Presents Initial Results from the Ongoing Rubraca® (rucaparib) TRITON Program in Metastatic Castration Resistant Prostate Cancer at ESMO 2018

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Clovis Oncology, Inc. (NASDAQ: CLVS) today announced initial data from its ongoing Phase 2 TRITON2 clinical trial of Rubraca at the ESMO 2018 Congress (European Society for Medical Oncology). The data show a 44% confirmed objective response rate (ORR) by investigator assessment in 25 RECIST* /PCWG3** response-evaluable patients with a BRCA1/2 alteration. The median duration of response in these patients has not yet been reached. In addition, a 51% confirmed prostate specific antigen (PSA) response rate was observed in 45 PSA response-evaluable patients with a BRCA1/2 alteration.
The TRITON2 results were the basis for Breakthrough Therapy designation for Rubraca as a monotherapy treatment of adult patients with BRCA1/2 mutated mCRPC who have received at least one prior androgen receptor (AR)-directed therapy and taxane-based chemotherapy, which was granted on October 2, 2018 by the U.S. Food and Drug Administration (FDA). These data will be highlighted in a poster authored by Dr. Wassim Abida, Medical Oncologist, Memorial Sloan Kettering Cancer Center, and principal investigator for the TRITON2 study. The data have been selected for a poster discussion session that will be led by invited discussant Dr. Joaquin Mateo, of the Prostate Cancer Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO) on 21 October at 09:15-9:40 CEST.
"Rubraca has previously demonstrated antitumor activity in its approved indications for women with advanced ovarian cancer," said Dr. Abida. "These new data show that Rubraca may also offer a new approach for the treatment of mCRPC associated with BRCA1 and BRCA2 alterations, with the potential to achieve a clinical response in patients with few remaining therapy options."
Patients enrolled in the TRITON2 study had received prior treatment with at least one androgen receptor (AR)-directed therapy and taxane-based chemotherapy and were screened for a deleterious germline or somatic alteration in BRCA1, BRCA2 or one of 13 other pre-specified homologous recombination (HR) genes. Study participants were allocated into three cohorts based on the type of gene alteration and disease status, which was determined by genomic sequencing and RECIST criteria, respectively. Each cohort received 600mg Rubraca twice daily and were grouped based on the following criteria: A) alteration in either BRCA1, BRCA2 or ATM genes, with tumors that can be measured with visceral and/or nodal disease; B) alteration in either BRCA1, BRCA2 or ATM genes, with tumors that cannot be measured with visceral and/or nodal disease, or C) alteration in another HR gene associated with sensitivity to PARP inhibition, with or without measurable disease. The primary study endpoints include confirmed ORR per RECIST/PCWG3 in patients with measurable disease at baseline and PSA response in patients with no measurable disease at baseline. Secondary endpoints include overall survival (OS), clinical benefit rate, and safety and tolerability.1
As of the visit cut-off date of June 29, 2018, 85 patients were treated with Rubraca; the overall median treatment duration was 3.7 (range, 0.5–12.9) months and median follow up was 5.7 (range, 2.6–16.4) months. The median treatment duration in patients with a BRCA1/2 alteration was 4.4 months (range, 0.5-12.0 months). Forty-six patients (54.1%) were evaluable for RECIST/PCWG3 response, including 25 patients with a BRCA1/2 alteration. By investigator-assessed RECIST/PCWG3, the confirmed ORR in patients with a BRCA1/2 alteration treated with Rubraca was 44.0% (11/25). Among the 45 evaluable patients with a BRCA1/2 alteration, 51.1% (23/45) had a confirmed PSA response (95% CI, 35.8–66.3).
Overall, the most common treatment-emergent adverse events (TEAEs) of any grade (CTCAE Grade 1-4) in all patients regardless of causality included asthenia/fatigue (44.7%, or 38/85), nausea (42.4%, or 36/85), anemia/decreased hemoglobin (22.4%, or 19/85) and constipation (28.2%, or 24/85). Five patients (5.9%) discontinued therapy due to a non-progression TEAE. One patient died due to disease progression.1
"We are very encouraged by these initial findings from the TRITON2 study, which demonstrate the potential of Rubraca to treat men with advanced prostate cancer whose disease has progressed after receiving multiple prior lines of therapy," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "PARP inhibitors are now a validated therapeutic class in oncology in multiple tumor types, and these new data underscore the benefit that Rubraca may provide for men with advanced, BRCA-mutant castration-resistant prostate cancer. Having recently received Breakthrough Therapy designation based on these data, we are committed to the rapid development of Rubraca for men with this very difficult-to-treat disease."
The poster discussion session also will include the first presentation of genomic profiling data based on tumor tissue and plasma cfDNA samples from the TRITON clinical program. The poster, authored by Dr. Simon Chowdhury, Consultant Medical Oncologist, Guy's Hospital & Sarah Cannon Research Institute and co-principal investigator for the TRITON clinical studies, will be included in the same poster discussion session as the TRITON2 data, led by invited discussant Dr. Joaquin Mateo, of the Prostate Cancer Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO). The poster discussion session takes place on 21 October at 09:15-9:40 CEST.
The data suggest cfDNA detected from plasma can be used to identify deleterious HR gene alterations in a manner that is less invasive than tumor tissue testing. Additionally, due to the invasiveness of tumor tissue sample collection, archival primary prostate samples are often used, and data suggest these samples are not representative of the somatic alterations which emerge in mCRPC.
In the study evaluation, patients' HR gene alteration status was determined by screening a total of 1,311 tumor and 638 plasma specimens, collected from a total of 1,516 patients to determine eligibility for TRITON2 and TRITON3. There was high concordance (74%) in identifying patients with deleterious BRCA1/2 mutations by both tissue and plasma sample. The results demonstrate that detecting genetic alterations within HR genes using cfDNA sequencing could prove to be a convenient method to identify patients who might be suitable candidates for treatment with Rubraca.2 Approximately 12% of men screened for the TRITON2 study were identified as having a BRCA1/2 alteration by plasma screening.
"Tumor tissue testing relies heavily on archival samples taken when a patient is newly diagnosed but may not capture all the alterations that emerge in patients with metastatic disease," said Dr. Chowdhury. "The screening data demonstrate that there is a high concordance between alterations detected in the tissue and plasma assays. Due to the less invasive nature of obtaining cfDNA through plasma testing, this method may be more suitable for both physicians and patients and may also identify more patients eligible for clinical trials of Rubraca."

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