Olaparib antitumor activity sustained across HRR gene subtypes in mCRPC

A gene-by-gene exploratory analysis from the phase 3 PROfound trial showed antitumor activity with the PARP inhibitor olaparib (Lynparza) across most of the 15 prespecified homologous recombination repair (HRR) genes evaluated in patients with metastatic castration-resistant prostate cancer (mCRPC).¹

Johann de Bono, MB CHB, PhD, MSC

“The results expand on the radiographic progression-free survival (rPFS) and overall survival (OS) results that had previously been reported for BRCA1 and/or BRCA2, ATM, and CDK12, and, as with other PARP inhibitor studies, show differential sensitivity to olaparib in the treatment of patients with distinct HRR alterations,” Johann de Bono, MB CHB, PhD, MSC, a co-principal investigator of the PROfound trial and lead author of the exploratory analysis said when sharing the findings during the 2021 Genitourinary Cancers Symposium.

“Activity was observed in patients with alterations in ATM, CDK12, and in some patients with other HRR gene alterations, supporting the need for further studies to assess genomic indicators of PARP sensitivity,” added de Bono, MB CHB, PhD, MSC, head of drug development at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust.

The PROfound trial enrolled patients with mCRPC who had alterations in at least 1 of 15 prespecified genes with a direct or indirect role in HRR and whose disease had progressed during previous treatment with a next-generation hormonal agents.²

Cohort A (n = 245) of the study consisted of patients with at least 1 alteration in BRCA1, BRCA2, or ATM, while cohort B (n = 142) comprised patients with at least 1 alteration in any of the other 12 prespecified genes: BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L. Baseline characteristics were well balanced across subgroups defined by the specific mutations.

Patients were randomly assigned 2:1 to receive either olaparib or the physician’s choice of enzalutamide (Xtandi) or abiraterone acetate (Zytiga). In cohort A, 162 patients received olaparib and 83 patients were assigned to control therapy. In cohort B, 94 patients received olaparib, while 48 patients were in the control arm.

Among patients in cohort A, 160 patients had a BRCA or BRCA2 alteration: 13 (8.1%) had a single alteration in BRCA1, 128 (80%) had a single alteration in BRCA2, and 19 (11.9%) had a co-occurring alteration. Of these 160 patients, 102 received olaparib and 58 were randomized to control. Also in cohort A, 86 patients had an ATM alteration, 62 of whom received olaparib and 24 of whom were randomized to control.

In cohort B, 89 patients had a CDK12 mutation, including 61 patients who received olaparib and 28 patients assigned to control. The remaining patients had alterations in BRIP1, BARD1, CHEK1, CHEK2, PALB2, PPP2R2A, RAD51B, RAD51D, and RAD54L.None of the patients included in the analysis had mutations in RAD51C or FANCL.

Overall, the median OS was superior with olaparib compared with control therapy in cohort A (31% reduction in the risk of death; 19.1 months vs 14.7 months; HR, 0.69; P = .02) and cohort B (14.1 months vs 11.5 months; HR, 0.96). Also of note, in cohort A the median rPFS was 7.4 months with olaparib compared with 3.6 months in the control arm (66% reduction in the risk of disease progression or death; HR, 0.34; P <.001).

The analysis presented at the GU symposium showed that the greatest benefit occurred in patients with BRCA1/2 mutations. In this group, there was a 78% (HR, 0.22) reduction in the risk of disease progression or death, and a 37% (HR, 0.63) reduction in the risk of death. The median rPFS was 9.8 months with olaparib versus 3 months in the control group and the median OS was 20.1 versus 14.4 months, respectively.

De Bono said that although the greatest activity in terms of changes in target lesions occurred in the BRCA1/2 population, “We also see impressive antitumor activity in the ATM loss population, and some antitumor activity in the CDK12 population.”

In patients with ATM loss, the median rPFS was 5.4 months with olaparib compared with 4.7 months in the control arm (HR, 1.04). The median OS was 18 versus 15.6 months, respectively (HR, 0.93). In the CDK12 group, the median rPFS was 5.1 months with olaparib versus 2.2 months in the control arm (HR, 0.74). The median OS was 14.1 versus 11.5 months, respectively (HR, 0.97).

De Bono also noted that he and his coinvestigators observed durable antitumor activity among patients with the other, rarer, evaluable HRR mutations, particularly PALB2; however, the PPP2R2A subgroup was the one exception. In these patients, De Bono explained that the HR for risk of disease progression or death was 6.61 and “preclinical studies did not support PARP inhibitor sensitivity.”

“PROfound is the first randomized trial to prospectively demonstrate rPFS and OS improvement in molecularly defined subsets of patients with prostate cancer,” De Bono concluded. “These findings support the importance of genomic testing to identify patients eligible to consider olaparib treatment.”

In the United States, the FDA approved olaparib in May 2020 for the treatment of adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone. The European Commission approved olaparib in November 2020. for the treatment of patients with BRCA 1/2–mutation positive mCRPC.

References

1. De Bono JS, Matsubara N, Penel N, et al. Exploratory gene-by-gene analysis of olaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): PROfound. J Clin Oncol 39, 2021 (suppl 6; abstr 126). doi: 10.1200/JCO.2021.39.6_suppl.126

2. Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer [published online September 20, 2020]. N Engl J Med. doi:10.1056/NEJMoa2022485