PROfound: Olaparib shows significant OS benefits in BRCA1/2 and/or ATM altered mCRPC
The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib was shown to prolong radiologic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC) harbouring alterations in homologous recombination repair (HRR) genes in the PROfound study. These positive results were reinforced by the final overall survival (OS) analysis of PROfound, presented at the European Society for Medical Oncology Virtual Congress 2020 (ESMO 2020), which support the implementation of genomic testing for mCRPC in clinical practice.
PROfound: Olaparib in mCRPC with HRR gene alterations
About 20 percent of mCRPC patients harbour alterations in HRR genes, most of which are BRCA1, BRCA2 or ATM mutations targeted by PARP inhibitors. [Cell 2015;161:1215-1228]
The phase III PROfound study evaluated the efficacy and safety of the PARP inhibitor olaparib in mCRPC patients with alterations in at least one of 15 prespecified HRR genes whose disease progressed on prior treatment with a next-generation hormonal agent (eg, abiraterone or enzalutamide). [N Engl J Med 2020;382:2091-2102]
Patients enrolled in the study were divided into two cohorts based on molecular status. Cohort A included 245 patients harbouring BRCA1, BRCA2 or ATM mutations, and cohort B included 142 patients harbouring at least one of 12 other genomic alterations (ie, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L).
Patients in both cohorts were randomized in a 2:1 ratio to receive olaparib 300 mg tablets BID or control therapy (either enzalutamide 160 mg QD, or abiraterone 1,000 mg QD plus prednisone 5 mg BID). Upon radiographic disease progression, patients in the control arm could cross over to receive olaparib if they had not received other subsequent anticancer therapy, had no unresolved grade ≥1 toxicity from previous therapy, and had agreed to continue attending the scheduled trial visits.
The study met its primary endpoint of prolonged rPFS in cohort A (median PFS, 7.4 months with olaparib vs 3.6 months with control; hazard ratio [HR], 0.34; 95 percent confidence interval [CI], 0.25 to 0.47; p<0.001), as reported previously.
Significant OS improvements with olaparib despite high crossover
Results of the final overall survival (OS) analysis, presented at ESMO 2020, showed a significant 31 percent improvement in OS with olaparib vs control in cohort A (median, 19.1 months vs 14.7 months; HR, 0.69; 95 CI, 0.50 to 0.97; p=0.0175). [de Bono J, et al, ESMO 2020, abstract 610O; N Engl J Med 2020, doi: 10.1056/NEJMoa2022485]
“The OS benefit in cohort A was observed despite having 67 percent of patients cross over from the control arm to the olaparib arm,” said investigator Dr Joaquin Mateo of Vall d’Hebron Institute of Oncology, Barcelona, Spain. “The benefit became more prominent after adjusting for the impact of crossover [HR, 0.42; 95 percent CI, 0.19 to 0.91]. This suggests that the actual treatment effect of olaparib is likely to be greater than what has been observed in the PROfound study.” (Figure 1)
Meanwhile, no significant OS benefit was observed with olaparib vs control in cohort B (median, 14.1 months vs 11.5 months; HR, 0.96; 95 percent CI, 0.63 to 1.49) or in the overall population (median, 17.3 months vs 14.0 months; HR, 0.79; 95 percent CI, 0.61 to 1.03). The HR for OS in cohort B and in the overall population was 0.83 (95 percent CI, 0.11 to 5.98) and 0.55 (95 percent CI, 0.29 to 1.06), respectively, after adjustment for crossover. (Figure 2)
“In an exploratory gene-level analysis, patients with tumours harbouring BRCA1/2 mutations [n=13 and 128, respectively] appeared to derive the greatest OS benefit from olaparib [HR for BRCA1, 0.42; 95 percent CI, 0.12 to 1.53] [HR for BRCA2; 0.59 95 percent CI, 0.37 to 0.95], but the OS improvement was not significant in those with ATM mutations [HR, 0.93; 95 percent CI, 0.53 to 1.75],” said Mateo.
“The safety profile of olaparib was consistent with the primary analysis and other phase III trials of olaparib. Grade ≥3 adverse events [AEs] were reported by 52 percent of patients in the olaparib arm vs 40 percent in the control arm. Anaemia was the most frequent grade ≥3 AE reported in the olaparib arm [23 percent],” he noted. “Treatment discontinuation due to AEs was required in 20 percent and 8 percent of patients, respectively.”
“PROfound is the first randomized study that prospectively demonstrated OS improvement in a molecularly defined subset of mCRPC patients, supporting the implementation of genomic testing in clinical practice,” concluded Mateo. “Prespecified sensitivity analyses, adjusting for the impact of crossover, suggest that the treatment effect of olaparib is likely to be greater than what has been observed in PROfound.”
“Additional studies are required to further delineate genomic indicators of response to PARP inhibitor therapy,” he advised.
Practice-changing results for BRCA1/2-positive mCRPC
“Results of the PROfound study are practice-changing for mCRPC patients with BRCA1/2 mutations who received prior standard treatment with an androgen receptor inhibitor [ARI] and a taxane,” said invited discussant Professor Henrik Grönberg of the Karolinska Institutet, Stockholm, Sweden. “As shown in cohort B of the study, olaparib is most likely not useful in mCRPC patients harbouring other driving mutations.”
“Patients in the control arm of PROfound were put on another ARI after disease progression on one ARI, leading to very low response rates. Hence, this approach is ineffective,” he pointed out. “In addition, evaluation of the OS benefits with olaparib became difficult after crossover.”
“Olaparib was generally well tolerated. Data on patients’ quality of life would allow for a more complete evaluation of its safety profile,” added Grönberg.