Olaparib regimen benefits men with metastatic castration-resistant prostate cancer
SAN FRANCISCO — The addition of olaparib to abiraterone acetate significantly extended radiographic PFS as first-line treatment for metastatic castration-resistant prostate cancer, according to an interim analysis of the randomized phase 3 PROpel study.
The findings, presented at ASCO Genitourinary Cancers Symposium, showed men experienced the benefit regardless of homologous recombination repair (HRR) gene mutation status. The combination also had a safety and tolerability profile consistent with that of the individual agents.
“[Metastatic castration-resistant prostate cancer] is really the lethal and most morbid state of prostate cancer,” Fred Saad, MD, FRCS, professor and chairman of urology and director of genitourinary oncology at University of Montreal Hospital Center, told Healio. “We have treatments available that have prolonged survival and helped to improve or maintain quality of life, but the improvements in survival and progression-free survival are relatively modest.
“The unmet need is to do better than we have for first-line [metastatic castration-resistant prostate cancer],” Saad added. “The reality is many of these patients won’t go beyond first-line treatment, so we have to do the very best we can upfront.”
Interactions of poly(ADP-ribose) polymerase (PARP) and androgen receptor signaling pathways have demonstrated a combined antitumor effect in preclinical studies, according to study background. In addition, a phase 2 study showed a combination of the PARP inhibitor olaparib (Lynparza; AstraZeneca, Merck) and abiraterone acetate (Zytiga, Janssen) prolonged radiographic PFS compared with abiraterone acetate alone among men with metastatic castration-resistant prostate cancer unselected by HHR status who had been treated with docetaxel (median, 13.8 months vs. 8.2 months; HR = 0.65; 95% CI, 0.44-0.97).
The double-blind, placebo-controlled PROpel study included 796 men undergoing first-line treatment for metastatic castration-resistant disease after primary androgen deprivation therapy failure. Researchers randomly assigned men to 1,000 mg once-daily abiraterone acetate plus 5 mg twice-daily prednisone or prednisolone with either 300 mg twice-daily olaparib (n = 399) or placebo (n = 397).
“Abiraterone is already our standard of care, [so] this was a high bar,” Saad said. “We wanted to include real-world patients ... and we did not make any effort to select patients based on mutational status.”
Investigator-assessed radiographic PFS served as the primary endpoint. Secondary endpoints included OS.
Results showed significantly longer radiographic PFS among men assigned the olaparib regimen (median, 24.8 months vs. 16.6 months; HR = 0.66, 95% CI, 0.54-0.81) regardless of whether they had mutations in HRR-associated genes detected through circulating tumor DNA testing.
“That’s an amazing number, because the trial that led to the approval of abiraterone showed about an 8-month improvement over a pure placebo,” Saad said.
A radiographic PFS sensitivity analysis by blinded independent central review yielded results consistent with those of the primary analysis, showing an 11-month improvement (HR = 0.61, 95% CI, 0.49-0.74).
Researchers observed improvement in the primary endpoint across all predefined subgroups, including among men with HRR gene mutations (HR = 0.5; 95% CI, 0.36-0.79) and those without them (HR = 0.76; 95% CI 0.59-0.97).
“Whether they had docetaxel in the hormone-sensitive setting or not, they benefited statistically significantly in independent groups,” Saad said. “Regardless of where the metastases lie ... regardless of age, [and] regardless of whether they harbored a mutation, which was almost 30% of patients — they benefited from the combination.”
OS data remained immature, with 228 deaths (28.6%). However, results showed a trend toward longer OS in the olaparib group (HR = 0.86; 95% CI, 0.66-1.12).
Results of secondary endpoints such as time to first subsequent treatment (HR = 0.74; 95% CI, 0.61-0.9) and time to second PFS or death (HR = 0.69; 95% CI, 0.51-0.94) suggested long-term benefit of the combination.
The most common grade 3 or higher adverse event, anemia, occurred among 15.1% of men in the olaparib group vs. 3.3% of the placebo group. Other grade 3 or higher adverse events in the olaparib group included hypertension (4%), urinary tract infection (2%) and fatigue (2%).
Researchers reported 13.8% of men who took olaparib discontinued the agent because of an adverse event, compared with 7.8% who discontinued placebo. However, the olaparib and placebo groups had similar rates of adverse events that resulted in abiraterone acetate discontinuation (8.5% vs. 8.8%).
“This combination makes sense biologically and now is confirmed in this clinical trial that it is effective with little added toxicity,” Saad said. “We now have maybe the first combination therapy for the all-comer population with metastatic [castration-resistant prostate cancer].”
References:
- Clarke N, et al. Lancet Oncol. 2018;doi:10.1016/S1470-2045(18)30365-6.
- Saad F, et al. Abstract 11. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.
Perspective
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With respect to PROpel, should one use a combination of abiraterone and olaparib as first-line therapy for all patients with metastatic [castration-resistant prostate cancer], given the results? I don’t think so. I think we should await OS data, as there is drug and financial toxicity with the combination. However, I will say the [radiographic] PFS appears to be quite outstanding.
I would like to have a better understanding of which, among all these patients, benefit the most and then perhaps the combination should be considered as one of many options for first-line metastatic [castration-resistant prostate cancer].
Perspective
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PARP inhibitors have shown significant efficacy in men with prostate cancer who have BRCA 1/2 or select other homologous repair deficiency (HRD) alterations. Importantly, olaparib conferred a survival benefit among men with metastatic castration-resistant prostate cancer in the phase 3 randomized PROFOUND study. However, HRD+ prostate cancer accounts for a minority, perhaps 15%, of patients.
Many preclinical studies have identified interactions between PARP and the androgen receptor, which may allow it to exert anti-prostate cancer effects in a broader population. For instance, PARP can occupy androgen receptor promoter regions and impacts expression of androgen receptor target genes, especially in the presence of androgen receptor variants. Thus, it is rational to study PARP inhibitors with androgen receptor-targeted therapy in a molecularly unselected population, as in the PROpel study.
Concern remains that the bulk of the benefit in this study may have been driven by the relatively large HRD+ subpopulation. This concern is especially prominent given the more negative results from the MAGNITUDE study of abiraterone with or without niraparib (Zejula, GlaxoSmithKline) in all comers with metastatic castration-resistant prostate, which were presented simultaneously. These early PROpel data are from an interim analysis, and the magnitude of benefit could deteriorate as the data mature, potentially regressing to nonsignificant.
Ultimately, OS remains the gold standard, and additional data will be critical before the results of PROpel can be applied in current practice. For now, PARP inhibitor therapy remains indicated only in men with HRD alterations, outside of clinical trials, although there is still great interest in extending the impact of these agents to more men with metastatic castration-resistant prostate cancer.
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Saad F, et al. Abstract 11. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 17-19, 2022; San Francisco.