SUMMARY
The TRITON3 study, a phase 3 open-label, controlled, randomized trial, Evaluated the safety and possible long-term efficacy of Rucaparib, an inhibitor of poly ADP-ribose polymerase [PARP], in men with metastatic castration-resistant prostate cancer (mCRPC) with deleterious BRCA and ATM gene alterations.[1] Patients with BRCA 1/2 or ATM gene alterations and disease progression after treatment with second-generation androgen receptor pathway inhibitors (ARPI) such as abiraterone and enzalutamide were included in this multi-center trial, which was carried across 143 sites spanning 12 countries.
Of the 4855 patients that underwent prescreening and screening, 405 were eligible and were randomly assigned in a 2:1 ratio (with an interactive response system) to receive either 600 mg of oral rucaparib twice daily (n = 270) or the physician’s choice amongst docetaxel, enzalutamide, or abiraterone (n = 135).
Imaging-based progression-free survival (PFS) was the primary efficacy outcome and was defined as the time from randomization to soft tissue or bone disease progression (RECIST 1.1/PCWG-3) or death, whichever came first. The study reported a longer median imaging-based PFS in the BRCA subgroup with rucaparib as compared to the control group (11.2 months vs. 6.4 months; hazard ratio [HR] = 0.50, P < 0.001). Similarly, a longer median imaging-based PFS was also noted in the intention-to-treat population (10.2 months vs. 6.4 months; HR = 0.61, P < 0.001). However, on analysing the ATM subgroup, a significant difference in the imaging-based PFS was not noted in the primary analysis.
Analysis of the secondary outcomes for rucaparib versus the control group revealed that the objective response rate in the BRCA subgroup and the ATM subgroup was 45% versus 17% and 0% versus 14%, respectively. The overall survival in the BRCA subgroup was 24.3 months versus 20.8 months (HR = 0.81, P < 0.21) and a 50% PSA response rate was seen in 55% of the patients with rupcarib as compared to 27% in the control group.
The most common adverse events in the rucaparib group were fatigue, nausea, and anemia. Treatment leading to discontinuation was seen in 15% in the rucaparib group versus 22% in the control group. Grade 3 complications were slightly more common in the rucaparib group (60% vs. 53%).
COMMENTARY
With the advent of ARPI, the management of mCRPC has shifted towards a combination approach whenever feasible. Both EAU[2] and NCCN[3] guidelines outline the role of genetic testing and molecular diagnostics in patients with metastatic prostate cancer. The impact of DNA damage response (DDR) pathways on the management of prostate cancer has been well documented. BRCA mutations can cause alterations in DDR in both the primary and mCRPC. The role of PARP inhibitors, especially suited for patients with germline BRCA 1/2 - deficient solid tumors, was first explored with the drug olaparib in 2009 in a Phase I clinical trial.[4] As the study showed a significant response in a patient with metastatic prostate cancer, further trials were performed. The PROfound trial was a landmark trial that demonstrated the efficacy of olaparib for the treatment of mCRPC in patients with homologous recombination repair mutations that have progressed on ARPI.[5]
Rucaparib is an oral PARP inhibitor, which was given an accelerated FDA approval on 15th May 2020 after the results of the Phase II TRITON2 study were published, for patients with BRCA 1/2 alteration in the mCRPC setting.
TRITON3 is a landmark trial that assessed the safety and efficacy of rucaparib, for the treatment of patients with mCRPC that have progressed on ARPI, with somatic/germline BRCA 1/2 mutations.
The study showed that the image-based PFS was significantly longer; however, a similar finding was not observed in the overall survival analysis. More than 50% of the patients reported fatigue and nausea, and anemia was recorded in 47%. Fifteen percent had to discontinue the treatment owing to the adverse events, and 3% had pulmonary embolism. These are points of concern and need further evaluation.
The investigators need to be congratulated for recruiting large number of patients and including docetaxel as a comparator drug along with the others, unlike the previously performed PROfound, IMbassador250, and the KEYNOTE-641 trials.
However, a few shortcomings were noted while assessing the results of the TRITON3 trial. Most of the recruited patients had a good Eastern Cooperative Oncology Group performance score of 0 or 1, unlike the real clinical practice, where a significant percentage of these patients have a poorer performance status. Also, the overall survival should have been the primary endpoint, as this is a landmark trial.
The biggest hindrance in our country lies in the cost and the availability of genetic testing and the procurement of the drug. The cost of genetic testing ranges from 20,000 to 30,000 INR, while the final market price of this medicine averages between 40,000–50,000 INR approximately, with variations depending on the pharmaceutical company (bdparib by BDR Pharmaceuticals International Pvt Ltd, nuparp by Zydus Cadila, rucaparib by Lupin Ltd). Besides, further studies are required to investigate the optimal sequencing of rucaparib and other treatments in this subset of patients. As yet, more mature data is required from this landmark trial to provide insights about the future prospects of rucaparib in the management of mCRPC.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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