Lynparza Significantly Improves Survival in Subset of Patients with Metastatic Prostate Cancer

Lynparza (olaparib) significantly prolonged overall survival (OS) compared with Xtandi (enzalutamide) or Zytiga (abiraterone) plus prednisone in men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in BRCA1, BRCA2 or ATM, and whose disease had progressed during previous treatment with a next-generation hormonal agent.

In particular, the risk of death was 31% lower with Lynparza than with control therapy despite substantial crossover from control therapy to Lynparza.

Updated findings from the randomized, open-label phase 3 PROfound trial were presented at the 2020 European Society for Medical Oncology Virtual Congress and were simultaneously published in The New England Journal of Medicine.

“Exploratory analysis suggests that patients with BRCA mutations achieve the most benefit and additional studies may be required to further delineate genomic indicators of PARP response, particularly for those with less common gene alterations,” Dr. Joaquin Mateo, of Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona, Spain, said during a virtual presentation of the updated OS findings.

“PROfound is the first randomized trial to prospectively demonstrate overall survival improvement in a molecularly-defined subset of prostate cancer, supporting implementation of genomic testing in daily clinical practice,” he added.

Study Outcomes

Median OS was superior with Lynparza compared with control therapy in group A (19.1 months versus 14.7 months) and group B (14.1 months versus 11.5 months).

The crossover-adjusted analysis included 86 of 131 patients (66%) in the control group who had crossed over to receive Lynparza, including 56 (67%) patients in group A. Patients were eligible for crossover if they had radiographic disease progression, no other subsequent anticancer therapy, any toxicities from prior therapy less than or equal to grade 1, and agreed to continue with the study visit schedule.

Median duration of treatment with Lynparza in patients who crossed over was 4.8 months, and median duration of treatment with control therapy was 3.9 months. The researchers noted that this was an investigator-assessed end point, which could mean the results are potentially subject to reporting bias. “Patients who crossed over from control therapy to receive olaparib had a shorter median duration of olaparib exposure (4.8 months) than those who were randomly assigned to receive olaparib (7.6 months). Thus, earlier treatment with olaparib may have an advantage over its use later in the disease course,” they wrote.

The safety profile of Lynparza appeared consistent with what was previously shown in the primary analysis. No cumulative toxic effects were observed during the extended exposure period.

Patients in the Lynparza group and those who crossed over to receive Lynparza reported anemia (39%), nausea (36%) and fatigue or asthenia (32%) as the most common side effects. Seven percent of patients discontinued Lynparza treatment because of anemia.

Patients with metastatic castration-resistant prostate cancer who had alterations in at least one of 15 prespecified genes with a direct or indirect role in homologous recombination repair (HRR) and whose disease had progressed during previous treatment with a next-generation hormonal agents were enrolled into the PROfound trial.

Group A consisted of 245 patients with at least one alteration in BRCA1, BRCA2 or ATM, while group B comprised 142 patients with at least one alteration in any of the other 12 prespecified genes.

Patients were randomly assigned to receive either olaparib or the physician’s choice of Xtandi or Zytiga. In group A, 162 patients received Lynparza twice daily and 83 patients were assigned to control therapy. In group B, 94 patients received the same Lynparza regimen while 48 patients were placed in the control arm.

Measuring imaging-based progression-free survival (PFS), or the time from the start of treatment until disease worsened, in group A was the primary goal of the study.

Imaging-based PFS was significantly longer in the Lynparza arm within group A compared with the control group (median, 7.4 months versus 3.6 months). In the initial analysis, a significant benefit was also observed with confirmed objective response rate and the time to pain progression.

“PROfound is the first positive phase 3 PARP inhibitor trial in metastatic castration-resistant prostate cancer, meeting its primary end point of prolonged radiographic progression-free survival for metastatic castration-resistant prostate cancer with alterations in BRCA1, BRCA2 or ATM progressing on prior next-generation hormonal agents and treated with olaparib versus with enzalutamide or abiraterone,” said Mateo, adding that these data continue to support the FDA’s approval of Lynparza in this setting earlier in 2020.