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Rucaparib pharmacokinetic analyses support use in mCRPC


Rucaparib pharmacokinetics in men with prostate cancer were comparable to those reported for women with ovarian cancer.

The amount of rucaparib (Rubraca) in patients’ blood did not affect the efficacy of the PARP inhibitor in patients with metastatic castration-resistant prostate cancer (mCRPC), according to population pharmacokinetic (PK) analyses from the phase 2 TRITON2 trial.1

The analyses, which were reported in a poster during the 2020 ESMO Congress, also found that there was not an association between a higher maximum concentration of rucaparib in a patient’s blood and a higher risk for most adverse events (AEs), including hematologic AEs.

“Rucaparib PK in men with CRPC was comparable to that observed in women with ovarian cancer. These analyses support the use of rucaparib in men with mCRPC using a starting dose of 600 mg BID,” the investigators wrote.

The open-label, multicenter, international TRITON2 study, enrolled male patients with mCRPC associated with 1 of 13 homologous recombination repair gene alterations. Patients had disease progression on androgen receptor (AR)–directed therapy and 1 prior taxane-based chemotherapy.

Based on the TRITON2 data, the FDA approved rucaparib in May 2020 for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)–associated metastatic mCRPC who have been treated with AR-directed therapy and a taxane-based chemotherapy.

The efficacy part of the PK analyses shared during ESMO measured the amount of rucaparib in patients’ blood using “steady state AUC normalized by actual dose for each patient up to the event of interest [AUCavg,ss].” Using statistical modeling, the investigators determined that there was not a statistically significant relationship between the AUCavg,ss and investigator-assessed objective response rate (P = .632).

Regarding safety, the analyses showed that there was not a statistically significant exposure-safety relationship for almost all AEs: grade ≥3 neutrophil count decrease (P = .449); grade ≥3 leucocyte count decrease (P = .200); grade ≥3 lymphocyte count decrease (P = .121); grade ≥3 platelet count decrease (P = .301); grade ≥3 hemoglobin decrease (P = .062); hemoglobin change from baseline (P = .167); grade ≥3 ALT increase (P = .571); and grade ≥3 fatigue/asthenia (P = .525).

There was, however, a correlation between rucaparib exposure and grade ≥2 creatinine increase. The investigators suggested in their abstract that, “This may be due to inhibition of renal transporters (eg, MATE1 and MATE2-K) by rucaparib rather than direct impact on renal function.”

Overall TRITON2 data

The overall efficacy and safety populations for TRITON2 included 115 BRCA-positive patients with or without measurable disease.2 The median patient age was 72 (range, 50-88), 74% of patients were white, and all except 2 patients had an ECOG performance status <2. The median baseline PSA was 61.1 ng/mL and 67% of patients had a Gleason score ≥8 at baseline. Across the population, 62 patients had measurable disease at baseline and 53 patients had nonmeasurable disease.

Patients were treated with rucaparib at 600 mg twice daily until radiographic progression or treatment discontinuation. Tumors were radiographically assessed every 8 weeks for 24 weeks, and then every 12 weeks. PSA assessments were performed every 4 weeks.

Twenty-seven (43.5%) of the 62 patients with measurable disease had confirmed ORRs per independent radiology review. The responses comprised 7 complete responses and 20 partial responses. Fifteen of the 27 responders had a duration of response ≥6 months. An additional 28 (45.2%) patients had stable disease, 6 had progressive disease, and 1 patient was not evaluable. Among all 115 patients, the confirmed PSA response rate was 54.8% (n = 63).

The overall safety assessment showed that 70 (60.9%) of the 115 patients experienced a grade ≥3 treatment-related adverse event (TEAE). The most common grade ≥3 TEAE was anemia/decreased hemoglobin (25.2%). TEAEs led to dose interruptions or reductions in 63.5% of patients, and discontinuations in 7.8% of patients. There was 1 patient TEAE-related death (acute respiratory distress syndrome).


1. Chowdhury S, Patnaik A, Campbell D, et al. Rucaparib population pharmacokinetics and exposure-response analyses in patients with metastatic castration-resistant prostate cancer (mCRPC) in TRITON2. Ann Oncol. 2020;31(4). Abstract: 659P.

2. Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration [published online August 14, 2020]. J Clin Oncol. doi: 10.1200/JCO.20.01035

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