Rucaparib in Metastatic Castration-Resistant Prostate Cancer With BRCA1/2 Alteration

[Balsam01]

TAKE-HOME MESSAGE

•The authors report outcomes of 115 men with metastatic castration-resistant prostate cancer with an associated BRCA1 (n=13) or BRCA2 (n=102) alteration (44 germline and 71 somatic) treated with rucaparib (a PARP inhibitor) as part of the open-label, phase II TRITON2 study. All men had received prior taxane-based chemotherapy for castration-resistant disease, as well as at least one prior next-generation androgen receptor–directed therapy (one-third had received two or more). The RECIST/Prostate Cancer Clinical Trials Working Group 3 objective response rate (the primary endpoint) was 43.5% and 50.8% by independent review and investigator assessment, respectively, and the confirmed PSA response rate was 54.8%. Objective response rates were similar among subgroups (groups based on number of prior therapies; germline or somatic alteration; BRCA1 or BRCA2), whereas the PSA response was higher among those with BRCA2 alterations. Radiographic progression–free survival was 9 months by independent assessment; overall survival data were not mature yet.

•Based on earlier reports from this trial, the FDA granted accelerated approval for rucaparib for this patient population in May 2020.

– Paul J. Hampel, MD

Oncology

Written by Oliver Sartor MD.

The new prostate cancer rucaparib data in patients with pathogenic BRCA alterations (germline or somatic) presented in the manuscript by Abida et al are important for several reasons. These data were pivotal for the FDA May 15, 2020, approval for rucaparib and represent an extensive effort by the talented investigators. All patients had metastatic CRPC and had been previously treated with both a taxane-containing regimen and a novel hormone such as abiraterone or enzalutamide. All patients had progressive disease at the time of trial entry and all patients had a pathogenic alteration in BRCA1 or BRCA2.

The primary input of the trial was radiographic response rate in those patients with measurable disease. There were multiple secondary endpoints, including confirmed PSA declines. The objective radiographic response rate as assessed by independent reviewers was 43.5%. The confirmed PSA decline rate of 50% or more was 54.8%. Approximately 25% of the men developed grade 3 or worse anemia, a known consequence of PARP inhibitors.

There now two PARP inhibitors approved by the FDA in advanced prostate cancer, with olaparib being approved after review of data from the PROfound trial. These two PARP inhibitors join pembrolizumab in the precision medicine armamentarium for advanced prostate cancer patients. Pembrolizumab is approved for those with MSI-high or mismatch-repair deficiency or a high tumor mutational burden.

Genetic testing is required for these therapies. For those selected patients who qualify for treatment, these new treatment options provide the opportunity for better therapeutic outcomes. Taken together, obtaining germline and somatic genetic assessment in advanced prostate cancer patients should be strongly considered for optimal patient care.

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.

Journal of Clinical Oncology.

Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration

J. Clin. Oncol 2020 Aug 14;[EPub Ahead of Print], W Abida, A Patnaik, D Campbell, et al

[j-o-h-n]

Pca patient lives matter............

Good Luck, Good Health and Good Humor.

j-o-h-n Friday 08/21/2020 1:06 PM DST