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As soon as Astrazeneca and Merck & Co revealed in February that Polo, the Lynparza pancreatic cancer study, had read positively the complete presentation of the data from this trial, it has become one of the best choices in this year's Asco conference.
In this case, only the main criterion of the study, progression-free survival, strongly favored Lynparza and the total lack of survival benefit became a black mark. Polo represents the first success of an inhibitor of Parp in pancreatic cancer. Companies can therefore hope that the benefit of the PFS will be sufficient to be approved.
Merck Chief Medical Officer Roy Baynes emphasized the importance of delaying the progression of pancreatic cancer. Advantage that this could delay the need for follow-up treatments. "This is not uncommon in the history of Parp," he said.
Meanwhile, Astra defended the SSP result as clinically significant, and said the operating system data had not yet reached maturity. However, neither company would say whether Polo would be used immediately to support a new regulatory filing.
Germina BRCA
Lynparza is already approved in various contexts of ovarian and bad cancer, but Polo has specifically tested it in subjects with BRCA-positive and germinal pancreatic cancer that still responded to the first-line platinum chemotherapy.
At the beginning of the year, a small, uncontrolled study of Rubraca de Clovis showed the potential of PPI inhibitors in a similar maintenance context. This, and Astra and Merck already revealing that Polo had read positively, highlighted the presentation of complete Polo data at Asco.
As promised, the result of the PFS greatly benefits Lynparza and the median probably does not tell the whole story. survival curves start to separate only after five months, and late separation generally indicates that undiscovered biomarkers are involved.
But the lack of overall benefit for survival is worrisome. However, it has already been argued that since pancreatic cancer is currently the domain of platinum toxic chemotherapy, a safety advantage alone would be promising.
Since the comparator Polo is not a chemotherapy, but a placebo, a direct benefit in terms of safety can not be evaluated. "The duration of treatment badigned to Lynparza was longer, which partly explains the rate of AE compared to placebo, but the rate of IE remained low and consistent with past experience" said a vice president of Astra, responsible for the Lynparza program. Advantage.
| Lynparza in the treatment of BRCA-positive pancreatic cancer (NCT02184195) | ||
|---|---|---|
| Lynparza | Placebo | |
| Median PFS * | 7,4mth | 3.8 months |
| Statistics for PFS | HR = 0.53 (p = 0.004) | |
| Median OS (46% maturity of the data) | 18.9 months | 18.1 months |
| Statistics for OS | HR = 0.91 (p = 0.68) | |
| QoL score change EORTC QLQ-C30 (higher will be high) | -1.20 | +1.27 |
| Grade ≥3 adverse events | 40% | 23% |
| Note: * main criterion. Source: Asco. | ||
To address the lack of benefits related to the SG, according to the investigators, 15% of placebo recipients who had progressed to receive a Parp inhibitor, and if they were getting a benefit, it could have been confusing.
A comparison between studies and the Rubraca trial also raises questions. For example, the median PFS with Rubraca was 9.1 months and that of six months about 70%, versus 7.4 months and 53% respectively at Polo. Of course, Rubraca's trial was much smaller than Polo's and was uncontrolled (AACR 2019 – The Rubraca trial suggests a place for Parps in pancreatic cancer, April 2, 2019).
Polo had scored 154 subjects. These came from 3,315 individuals who had initially been screened for BRCA mutation carriers and who had not progressed. An essential difference between this trial and the Rubraca trial is that it also included positive subjects for PALB2, an even rarer genetic mutation.
Polo has not prospectively recruited subjects carrying the PALB2 genetic mutation. Approximately 6-8% of pancreatic cancers carry BRCA or PALB2 mutations, and Polo investigators reported that 7.5% of initially screened subjects were positive for BRCA germline; the rest of the excluded had already progressed during the chemo.
Pancreatic cancer is hardly in Lynparza's prediction of badysts, which probably reflects the extremely insoluble nature of the disease. according to EvaluerPharma consensus on the sellers side, the drug will generate combined revenue of $ 2.8 billion in 2024.
Beyond Polo, no other major studies of Parps in pancreatic cancer has involved the industry. It seems unlikely that Asco data will change this state of affairs.
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