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Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1or BRCA2 gene alteration

  • Wassim Abida,
  • Akash Patnaik,
  • David Campbell,
  • Jeremy Shapiro,
  • Alan H. Bryce,
  • Ray McDermott,
  • Brieuc Sautois,
  • Nicholas J. Vogelzang,
  • Richard M. Bambury,
  • Eric Voog,
  • Jingsong Zhang,
  • Josep M. Piulats,
  • Charles J. Ryan,
  • Axel S. Merseburger,
  • Gedske Daugaard,
  • Axel Heidenreich,
  • Karim Fizazi,
  • Celestia S. Higano,
  • Laurence E. Krieger,
  • Cora N. Sternberg,
  • Simon P. Watkins,
  • Darrin Despain,
  • Andrew D. Simmons,
  • Andrea Loehr,
  • Melanie Dowson,
  • Tony Golsorkhi,
  • Simon Chowdhury,
  • on behalf of the TRITON2 investigators

Publication: Journal of Clinical Oncology, August 2020

Purpose

BRCA1 or BRCA2 (BRCA) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from patients with mCRPC associated with a BRCA alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study.

Methods

We enrolled patients who progressed after one to two lines of next-generation androgen receptor–directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious BRCA alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate.

Results

Efficacy and safety populations included 115 patients with a BRCA alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic BRCA alteration and for patients with a BRCA1 or BRCA2 alteration, while a higher PSA response rate was observed in patients with a BRCA2 alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients).

Conclusion

Rucaparib has antitumor activity in patients with mCRPC and a deleterious BRCA alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.

Commented by Dr. Ploussard

Response to third-line therapies in men with progressing mCRPC after next-generation AR-directed therapy and taxane-based chemotherapy remains poor, highlighting the need for new life-prolonging strategies. This desirable improvement might be achieved by a better selection of patients based on predictive biomarkers such as BRCA alteration. Approximately 10-15% of men with mCRPC harbor a BRCA alteration and could benefit from PARP inhibitor treatment inducing tumor cells lethality in case of homologous recombination–directed DNA damage repair deficiency. In the phase II TRITON2 trial, rucaparib has been evaluated in mCRPC patients with a deleterious alteration in BRCA  gene and who have progressed after next-generation AR-directed therapy and a taxane-based chemotherapy. A starting dose of 600 mg was given twice daily with dose reductions if grade ≥ 3 or persistent grade 2 adverse events.

The primary end point was objective response rate and secondary end points included duration of response, PSA response ≥ 50%, time to PSA progression, radiographic progression-free survival (rPFS), overall survival (OS), and safety. Patients were screened for somatic or germline alteration in BRCA1 and  BRCA2, through central genomic testing of plasma or tumor tissue. Overall, 115 patients received ≥ 1 dose of rucaparib. Germline and somatic alterations were reported in 44 and 71 patients, respectively. Median treatment duration was 8.1 months with a median follow up of 17.1 months. At last follow-up, one fourth of patients remained on active treatment.

PSA response was observed in 54.8% and median time to PSA progression was 6.5 months. Median rPFS was 9.0 months. Interestingly, 8 patients had a confirmed complete response in soft-tissue disease. OS data was not mature at the time of the publication. One adverse event occurred in almost all patients and grade ≥ 3 toxicity was reported in 61% (fatigue, nausea, and anemia mainly). Treatment interruption due to adverse effects occurred in 65 patients (41% of dose reductions).

This study confirms the clinical activity of PARP inhibitors in mCRPC patients with DDR gene alteration. Rucaparib demonstrated significant radiographic and PSA responses, including complete responses in soft-tissue disease. The safety profile was in line with that observed in other cancers’ rucaparib studies and in other PARP inhibitors studies in prostate cancer.

The phase III TRITON3 study (NCT02975934) is ongoing to confirm the clinical benefit of the drug by randomizing patients to receive rucaparib or another therapy according to the physician’s choice (next-generation AR-directed therapy or docetaxel). This phase II study also reinforces the importance of genomic screening (germline and/or somatic) to identify men who may benefit from these biomarker-based treatments.