PARP Inhibition in Metastatic CRPC: The PROfound and TRITON2 Studies


Expert perspectives on the PROfound and TRITON2 studies of olaparib and rucaparib, respectively, in metastatic castration-resistant prostate cancer.


Alan Bryce, MD: I'm going to go over the PROfound Study data and then we're going to go over [the] TRITON2 [study]. The PROfound Study was a phase 3 study looking at olaparib versus physician's choice of therapy in a mixed population of patients with mCRPC [metastatic castration-resistant prostate cancer]. And I'll explain that a bit here. Everyone had to qualify as having 1 of the qualifying HRR [homologous recombination repair] gene mutations. In cohort A was BRCA1, BRCA2, and ATM. In cohort B were all of the other qualifying aberrations which you see listed on the bottom of the slide in blue. And then, within each cohort, patients were randomized to olaparib versus physician's choice in a 2-to-1 randomization, and the physician's choice was either abiraterone or enzalutamide—whichever drug the patient hadn't previously received. Looking at the efficacy for PFS [progression-free survival] and OS [overall survival] in both cases, in cohort A, it strongly favored the olaparib arm. Thus, rPFS [radiographic PFS], the hazard ratio was 0.34. It doesn't get much better than that, right? That's beautiful. And then the OS. Here again, the hazard ratio is 0.69; 19 months versus 14.7 months—strongly positive for both primary end points. You can see the overall response rate was 33% with olaparib versus 2% in the control group. Here again, when you use ABI [abiraterone] or ENZA [enzalutamide] after ENZA or ABI, you don't get a lot of response. Median time to pain progression—course, it's a secondary end point [and] goes right along with the PFS and OS end points, thus strongly favoring olaparib. When we look at the safety, you do see some increased adverse events of Grade 3 or higher in olaparib. It has some myelosuppression. But you can see [that] these are fairly modest numbers. Nothing too dramatic. [It is] very manageable for an oncologist.

Ultimately, olaparib was approved by the FDA [Food and Drug Administration] in May 2020 specifically for men with mCRPC with a deleterious or suspected deleterious HRR gene mutation. And in fact, it's really the whole list that you saw there on the first slide who had been previously treated with enzalutamide or abiraterone. [There was] no requirement for a prior taxane. Then, in November 2020, the FDA approved the companion diagnostic, which is the FoundationOne Liquid CDx assay. For rucaparib, we have the TRITON2 study so far. TRITON3 is not yet reported. TRITON2 was the phase 2 single-arm study of rucaparib in men who had a qualifying deleterious HRR gene alteration, had been treated with 1 to 2 prior lines of an androgen receptor pathway inhibitor, and had received 1 prior line of taxane-based chemotherapy. These are later patients than we saw in the PROfound Study, for the most part. Patients were treated; everyone received rucaparib at the standard dosing until radiographic or unequivocal clinical progression or toxicity. The primary end point was in cohort A, looking at patients with measurable disease. They were looking at the overall response rate. This is really the outcome the FDA wanted to see for initial approval. And then, for patients without measurable disease, it's the confirmed PSA [prostate-specific antigen] response rate, the PSA-50 rate. When you look at the characteristics of patients with a BRCA1 or BRCA2 mutation, so 1781 patients screened, 209 enrolled, 115 had a BRCA alteration at screening. You can see here germline was approximately 38%. Somatic was approximately 61%. Again, the germline is only capturing less than 40%, so we want to look at the somatic. BRCA2 outnumbers BRCA1 by about 8 to 1, and that's consistent with other data sets. It's usually 5 to 10 times higher—something in that ballpark.

Early on, we were asking a lot of questions about zygosity; biallelic loss versus monoallelic loss and where the data was available, because it wasn't available in all patients, but you see biallelic loss happening more commonly in the BRCA2 patients. About 33% of the patients versus 6% [who were] monoallelic. [There’s] a little bit of a different distribution in BRCA1, but the numbers were so small, I'm not sure you'd draw any conclusions there. In looking at the radiographic response to the primary end point, the complete response [CR]—the overall response rate was over 50%: 50.8% of patients, so 33 out of 65. Complete response of 6.2, which really means they only had soft tissue disease—not bone disease, because there's no CR in the bone metastases patients. Partial response is 45%: 44.6%. An additional 38.5% with stable disease. And then, looking at the safety summary, again, you see a fairly safe drug, but nevertheless, the Grade 3 treatment immersion [for] adverse events was 52.9%. Treatment interruption, 48.2%. Just under 30% of patients would get a dose reduction. Only 6% had discontinuation due to toxicity. Ultimately, rucaparib was approved by the FDA. Also, in May 2020, a couple of days before the olaparib for deleterious BRCA-mutated metastatic CRPC in patients who had received at least one AR [androgen receptor]-directed therapy and 1 taxane-based chemotherapy. Thus, a different label than we see with olaparib, right? More restricted in the mutation and more prior lines of therapy required. And then, here again, FoundationOne Liquid CDx was eventually approved as a companion diagnostic.

Transcript edited for clarity.

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