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Drug Combination Shows Promise in Advanced Prostate Cancer

CHICAGO — Adding the poly ADP ribose polymerase (PARP) inhibitor olaparib (Lynparza, AstraZeneca) to the androgen synthesis inhibitor abiraterone acetate (Zytiga, Janssen) significantly improves progression-free survival (PFS) in men with advanced prostate cancer over abiraterone alone, UK researchers have discovered.

Studying 142 patients with metastatic castration-resistant prostate cancer (mCRPC), Dr Noel Clarke, The Christie and Salford Royal Hospitals, Manchester, found that those given the combination were 35% less likely to experience progression than those given just abiraterone, although there was no overall survival benefit.

Interestingly, the improvement in PFS with combination therapy was seen regardless of whether or not the patients had homologous recombinant repair (HRR) gene mutations, which have been identified as a key potential mechanism of action for PARP inhibitors.

The new data were presented here at the American Society of Clinical Oncology (ASCO) 2018 Annual Meeting. The study was also simultaneously published in The  Lancet Oncology.

'Significant Radiological Progression-Free Survival Benefit'

Clarke told the audience: "What we have shown in our study is that olaparib plus abiraterone provided a significant radiological progression-free survival benefit to mCRPC patents who had previously received docetaxel [Taxotere, Sanofi-Aventis] compared with abiraterone alone."

While Clarke acknowledged that the benefit came at the expense of "an increased incidence of adverse events compared with abiraterone alone, particularly cardiac events", he said that, based on their findings, the group has planned a phase 3 trial to test the combination further.

In an editorial accompanying the paper, Dr Emmanuel Antonarakis, from the Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore in the US, questioned, however, the way in which HRR status was defined in the study, and that it was underpowered to detect a difference based on HRR status.

Moreover, the low prevalence of mutations they detected, at 15%, suggests either that mutations were missed or that the men were potentially "homologous repair proficient".

He notes that there are numerous potential explanations for the "seemingly paradoxical results" seen in the study, but that "clearly, larger prospective and biomarker-stratified randomised trials are needed" to test the notion of synergy between the two drugs.

"Clarke and colleagues' study certainly provides the impetus to explore this intriguing possibility further."

Clarke began his presentation by noting that PARP inhibition plays an important role in blocking DNA repair pathways in cells that harbour HRR defects.

He said that there is also evidence that the combination of PARP inhibition and abiraterone works in a synergistic manner, with PARP involved in androgen-receptor dependent transcription and abiraterone inducing HRR deficiency.

The basis for our trial is to put this combination together to assess the synergy in relation to anti-tumour activity.

Study Design

The current study was therefore designed to assess the synergy in anti-tumour activity between the two approaches in 142 mCRPC patients previously treated with docetaxel who had received ≤2 prior lines of chemotherapy and who had not been treated with second-generation anti-hormonal agents.

The patients were randomised in a 1:1 fashion either to olaparib 300 mg plus abiraterone 1000 mg or to placebo plus abiraterone 1000 mg. They were treated until disease progression, with the primary endpoint being investigator assessed radiologic PFS.

While the two groups were well matched overall, patients given combination therapy were slightly older, at a median age of 70 years versus 67 years for abiraterone monotherapy.

The combination group also had a higher median prostate specific-antigen concentration, at 86 µg/L versus 47 µg/L in the monotherapy group, and were more likely to have 5–9 bone metastases, at 55% versus 35%.

Clarke said that patients given combination therapy had a significantly longer radiologic PFS than those given abiraterone alone, at a median of 13.8 months versus 8.2 months and a hazard ratio (HR) of 0.65 (p=0.034).

Next, the team performed HRR mutation testing, although that was not included in the initial assessment, with the possibility to test tumour samples, blood samples for germline analysis or plasma samples for circulating tumour DNA in all 142 patients.

The tests yielded biomarker data in 136 (96%) patients, with 21 (15%) found to have HRR mutations.

Analysis revealed differences in the hazard ratios for radiologic PFS for combination versus monotherapy arms between patients with HRR mutations (HR 0.74) those with partially characterised HRR mutations (HR 0.67) and those without such mutations (HR 0.52).

"This is the first study to show, in an unselected group of patients, that there was a differential effect from the combination of olaparib and arbiraterone by comparison with monotherapy with abiraterone," Clarke said.

There were no significant differences between combination and monotherapy arms in terms of secondary efficacy endpoints, such as the time to second PFS (p=0.28) or in overall survival (P=0.66).

There were also no complete responses in either arm. However, patients given olaparib with abiraterone had more than twice the rate of stable disease compared with those given abiraterone alone, at 48% versus 21%.

In contrast, monotherapy patients were more than twice as likely to have progressive disease, at 47% versus 21% in the combination therapy group.

As expected, combination therapy patients had, compared with those given monotherapy, a higher rate of any adverse events, at 93% versus 80%, a higher rate of grade ≥3 adverse events, at 54% versus 28%, and a higher rate of serious adverse events, at 34% versus 18%.

Specifically, olaparib plus abiraterone patients were more likely to experience nausea and substantially more likely to have anaemia, and were more likely to have serious cardiovascular events such as myocardial infarction, fatal cardiac failure, and fatal ischaemic stroke, than those treated with abiraterone alone.

'Surprising Outcome'

Discussing the findings following their presentation, Dr Anthony Joshua, The Kinghorn Cancer Centre, St. Vincent's Hospital Sydney, New South Wales, Australia, said the study "has given us perhaps a surprising outcome that has led us to re-evaluate some of our perceptions of what HRR means in prostate cancer and perhaps to re-evaluate the tests that we use to define HRR prostate cancer".

However, he pointed out that primary endpoint was not centrally adjudicated, and that the patient population "does not necessarily represent contemporary practice", and the results raise questions about why they do not reflect those of previous studies using similar treatment combinations.

The apparent treatment effect in patients without HRR mutations is also notable, and Joshua urged that "no definitive conclusions" be drawn from the results, "based on this small sample size, as well as due to issues in sampling tumour heterogeneity potentially confounding the result".

The choice of genes, cut-offs, and criteria used in the study is also questionable, particularly as the panels used to detect HRR mutations only partially overlap with those used in previous trials.

"These and other questions mean that the field is wide open and more data will be needed, with robust sampling and sequencing from upcoming academic and commercial efforts," Joshua said.

The study was funded by AstraZeneca.

Clarke declares Honoraria from Astellas Pharma; AstraZeneca; Bayer; Ferring; ipsen; Janssen-Cilag; Sanofi; Consulting or Advisory Role with Astellas Pharma; Bayer; Ferring; Janssen-Cilag; Sanofi; Speakers' Bureau with Astellas Pharma; Astellas Pharma; Janssen-Cilag; Janssen-Cilag; Research Funding with Astrazeneca (Inst); Travel, Accommodations, Expenses with Astellas Pharma; AstraZeneca; Bayer; Ferring; Ipsen; Janssen-Cilag; Sanofi.

 Antonarakis is a paid consultant or advisor to Janssen, Astellas, Sanofi, Dendreon,

Medivation, ESSA, AstraZeneca, Clovis, and Merck. He has received research

funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon,

Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis, and Merck.

He is the co-inventor of a biomarker technology that has been licensed to Qiagen.

This work was partially supported by the National Institutes of Health (P30

CA006973) and the US Department of Defense (W81XWH-16-PCRP-CCRSA).

 Joshua has no disclosures.

 American Society of Clinical Oncology (ASCO) 2018 Annual Meeting. Presented June 4, 2018. Abstract 5003.

Lancet Oncol 2018. Doi: 10.1016/ S1470-2045(18)30365-6 Paper