Rucaparib Boosts Radiographic Progression-Free Survival in Metastatic Castration-Resistant Prostate Cancer

Alan H. Bryce, MD

Compared with chemotherapy or second-line androgen deprivation therapy (ADT), single-agent rucaparib significantly improved radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (CRPC) harboring BRCA or ATM mutations, according to findings from the phase 3 TRITON3 trial (NCT02975934).¹

Topline data showed that patients with BRCA-mutated CRPC treated with rucaparib (n = 201) achieved a median rPFS of 11.2 months. For patients in the control group, rPFSwas 6.4 months (n = 101; HR, 0.50; 95% CI, 0.36-0.69; P < .0001). For patients with ATM mutations, rucaparib (n = 69) induced a median rPFS of 8.1 months vs 6.8 months for the control group (n = 34; HR, 0.97; 95% CI, 0.59-1.52; P = .8421).

Among the intention-to-treat (ITT) population, inclusive of those with BRCA or ATM mutations, those in the rucaparib arm (n = 270) experienced a median rPFS of 10.2 months, compared with 6.4 months for those in the control arm (n = 135; HR, 0.61; 95% CI, 0.47-0.80; P = .0003).

“We believe that the positive results from TRITON3 further demonstrate the important role that [rucaparib] can play as a treatment option for men with metastatic CRPC associated with homologous recombination deficiency, and we look forward to submitting these data to the regulatory authorities in the US during [the first quarter of] 2023,” Patrick J. Mahaffy, president and chief executive officer of Clovis Oncology, stated in a press release.

“Not only does this provide a potential treatment option for eligible men with earlier stage disease, but it is the first and only PARP inhibitor that has demonstrated superior rPFS compared to chemotherapy, which is today the standard of care for these patients.”

In May 2020, the FDA granted rucaparib accelerated approval for the treatment of adult patients with BRCA mutation (germline and/or somatic)—associated metastatic CRPC who have been treated with androgen receptor–directed therapy and a taxane-based chemotherapy, based on prior data from the phase 2 TRITON2 trial (NCT02952534).²

The multicenter, open-label, randomized TRITON3 trial is a confirmation study for the current accelerated approval, and it will also serve as the basis for a supplemental new drug application for label expansion in the United States.

The trial enrolled patients who were at least 18 years old with histologically or cytologically confirmed, chemotherapy-naïve metastatic CRPC harboring a BRCA1/2 or ATM mutation. Patients were also required to be surgically or medically castrated; be eligible for physician’s choice of comparator treatment with abiraterone acetate (Zytiga), enzalutamide (Xtandi), or docetaxel; and have disease progression following treatment with 1 next-generation androgen receptor–targeted therapy.³

Key exclusion criteria included an active second malignancy except for non-melanoma skin cancer, carcinoma in situ, or superficial bladder cancer; prior treatment with a PARP inhibitor; prior chemotherapy for metastatic CRPC; or symptomatic and/or untreated central nervous system metastases.

Enrolled patients were randomly assigned to receive oral rucaparib daily or physician’s choice of treatment with abiraterone acetate, enzalutamide, or docetaxel.

Along with the primary end point of rPFS, secondary end points included overall survival (OS), objective response rate, duration of response, time to prostate-specific antigen (PSA) progression, PSA response, patient-reported outcomes, clinical benefit rate, and safety.

An interim analysis of OS in the BRCA-mutation subgroup and ITT population favored rucaparib, though data were not yet mature. Mature OS data from the ATM-mutation subgroup favored the control arm.

Regarding safety, findings from TRITON3 were consistent with rucaparib labeling. The most common treatment-emergent adverse effects (TEAEs) of grade 3 or higher for patients treated with rucaparib on the study included anemia/decreased hemoglobin (23.7%), neutropenia/decreased neutrophil count (7.4%), asthenia/fatigue (7.0%), thrombocytopenia/decreased platelet count (5.9%), and increased ALT/AST (5.2%).

TEAEs led to treatment discontinuation in 14.8% of patients who received rucaparib compared with 21.5% of patients in the control arm.

“Men with this type of metastatic prostate cancer want to get their genetically targeted therapy as early as possible, and this trial clearly shows the value of rucaparib as a treatment for these men,” Alan H. Bryce, MD, chair of the Division of Hematology and Medical Oncology at the Mayo Clinic and principal investigator of the TRITON3 trial, stated in a press release. “A key point is that rucaparib can replace chemotherapy in this setting. The current standard of care for these men is chemotherapy with docetaxel, and rucaparib is the only PARP inhibitor which has beaten a docetaxel-containing control arm in a clinical trial.”

References

1. TRITON3 phase 3 trial of Rubraca® (rucaparib) achieves primary endpoint in men with metastatic castration-resistant prostate cancer with BRCA Or ATM mutations. News release. Clovis Oncology. October 3, 2022. Accessed October 3, 2022. https://bit.ly/3fFdBgz
2. Rubraca® (rucaparib) approved in the U.S. as monotherapy treatment for patients with BRCA1/2-mutant, metastatic castration-resistant prostate cancer (MCRPC) who have been treated with androgen receptor-directed therapy and a taxane-cased chemotherapy. News release. Clovis Oncology. May 15, 2020. Accessed October 3, 2022. https://bit.ly/2z0rMrK
3. A study of rucaparib versus physician's choice of therapy in patients with metastatic castration-resistant prostate cancer and homologous recombination gene deficiency (TRITON3). ClinicalTrials.gov. Updated March 24, 2022. Accessed October 3, 2022. https://clinicaltrials.gov/ct2/show/NCT02975934