ESMO 2018: Preliminary Results From TRITON2: A Phase II Study of Rucaparib in Patients with mCRPC Associated with Homologous Recombination Repair Gene Alterations

Munich, Germany (UroToday.com) Patients with inherited mutations in DNA repair genes such as BRCA2 have an association with increased risk of lethal prostate cancer. In a multicenter study incorporating 7 databases of patients with metastatic prostate cancer, 11.8% percent of patients were found to have germline DNA repair genes1. In another cohort of patients, 22.7% of patients had alterations in DNA repair and DNA recombination genes2.
TOPARP demonstrated that patients with DNA repair defects may be sensitive to poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibition3. In a small phase II trial in patients with mCRPC, 50 heavily pretreated patients were given olaparib. They pre-defined a biomarker-positive cohort of patients who had homozygous deletions, deleterious mutations, or both in DNA-repair genes (BRCA2, ATM, FANCA, CHEK2, BRCA1, PALB2, HDAC2, RAD51, MLH3, ERCC3, MRE11, NBN). Amongst the biomarker-positive group, 88% (14/16) patients had a response to olaparib, compared with 6% (2/33) of patients who were biomarker negative. A number of phase II and phase III studies are now ongoing investigating the role of single agent and combination therapies with PARP inhibitors. This study adds to that body of literature, with the use of rucaparib in patients with mCRPC.

TRITON2 evaluates the efficacy of rucaparib 600 mg BID for patients harboring a deleterious germline or somatic alteration in BRCA1, BRCA2 or 1 of 13 other prespecified homologous recombination repair (HRR) genes. 1-2 lines of prior androgen directed therapy and 1 line of prior taxane-based chemotherapy were permitted. At the time of this unplanned interim analysis, 85 patients have been enrolled. A total of over 150 patients are planned before completion of the study. Of these 85 patients, 45 have a BRCA1/2 alteration, 18 have an ATM alteration, 13 have a CDK12 alteration, and 9 have other mutations in the HRR pathway. 46 of the 85 patients have measurable disease and more than 16 weeks follow up.

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In terms of adverse events, the most common grade 3/4 event was anemia which occurred in 15% of patients. Half of the patients (52.9%) had a treatment interruption due to a treatment-related adverse event but most of these patients were able to restart therapy with dose reductions. Only 6% of patients had an adverse event which led to therapy discontinuation. There was one death reported due to a treatment-emergent adverse event.

In terms of efficacy, for the patients with BRCA1/2 alteration, there was a 44% confirmed overall response rate and 51% confirmed PSA response rate. The discussant noted that while this is an interim unplanned analysis, these numbers compare very favorably to the results from Cougar 3014 (Abiraterone for mCRPC after chemotherapy) and AFFIRM5 (Enzalutamide for mCRPC). 

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Unfortunately, patients harboring an ATM alteration did not receive any benefit. There were 0/18 confirmed PSA responses in this biologic subset of patients, and 0/5 confirmed RECIST responses. Of note, the investigators used a gene hierarchy when classifying response. For example, if a patient had both a BRCA1 loss and ATM loss, they would be counted in the BRCA1 cohort. Thus, it is possible that patients with ATM loss had a response, but they would have also had a BRCA mutation and thus not counted in the ATM cohort. While this study had 0 responses in the ATM cohort, 4 of the 6 patients with an ATM alteration were documented to have a response in TOPARP3.

Results for CDK12 were also reported. There were 0 out of 8 objective responses per RECIST and only 1 of 13 confirmed PSA responses. The investigators have stopped enrolling in the CDK12 cohort. UrotToday ESMO2018 TRITON2 3

Several studies have now demonstrated that the prevalence of BRCA1/2 defects in CRPC is around 10-12%. This study provides further evidence that BRCA1/BRCA2 germline or somatic alterations may sensitize tumors to PARP inhibition and rucaparib here demonstrates efficacy with robust radiographic and PSA responses. This early data compares favorably to other available therapies in this heavily pretreated population of patients with mCRPC who have had prior exposure to docetaxel.   

Important questions to consider in the future in this subset of patients is when we should be performing genomic testing to determine if patients qualify for PARP inhibition. For patients with germline mutations, the timing may not be as relevant but may matter for patients who develop somatic mutations. Metastatic biopsies are challenging in the population of patients with CRPC as most patients have a bone-only disease, which is technically challenging to biopsy and also frequently low yield in terms of adequate tumor sampling. Data from this ESMO conference show that circulating tumor DNA testing is feasible for our patients with both CRPC and metastatic CSPC (Abstract 796PD, Detection of circulating tumor DNA in de novo metastatic castrate-sensitive prostate cancer, Struss et al). 

An additional point of controversy exists over whether or not DNA repair mutations are necessary for tumor response to PARP inhibitors for patients with mCRPC. Data from this abstract and TOPARP show that patients harboring these mutations are sensitive to PARP inhibition but do not necessarily answer the question of whether or not they may be helpful for other patients. During ASCO 2018, Dr. Clarke presented results from a phase II study of patients with mCRPC randomized to olaparib + abiraterone vs placebo + abiraterone. In all patients, there was an improvement in radiographic progression-free survival for all patients, regardless of DNA repair defect status. Results were controversial and a phase III study is planned to help answer this question. Several phase II studies are also underway investigating PARP inhibitors in combination with immunotherapy and chemotherapy.
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Presented by: Wassim Abida, MD, Memorial Sloan Kettering Cancer Center, New York, US

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany 

References:
1. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. New England Journal of Medicine 2016;375:443-53.
2. Robinson D, Van Allen EM, Wu Y-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161:1215-28.
3. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. New England Journal of Medicine 2015;373:1697-708.
4. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. The New England journal of medicine 2011;364:1995-2005.
5. Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine 2012;367:1187-97.
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