How well do cancer drugs really work?

Only a third of USA-approved oncology drugs seem to improve overall survival. This is the sobering conclusion of a retrospective analysis of US approvals.

The most important surrogate parameters in oncology:

• Overall Response Rate (ORR)
• Complete Response (CR)
• Progression Free Survival (PFS)
• Recurrence Free Survival (RFS)
• Event Free Survival (EFS)

Gold standard: overall survival

The gold standard for demonstrating the efficacy of oncological drugs is overall survival (OS). Surrogate parameters (surrogatum = replacement) are only used as auxiliary parameters if the actual clinically relevant endpoint (e.g. mortality) is difficult to determine. However, the FDA (US Food and Drug Administration) has steadily expanded their use in recent years, so that a large proportion of approvals in the oncology sector are now based on them.

Researchers from the USA have investigated the consequences of this for the efficacy of the drugs. Specifically, they wanted to know:

1. How often cancer drugs have been approved on the basis of OS or surrogate markers in the last two decades.
2. How many approvals based on surrogate markers were subsequently tested for their OS benefit.
3. What percentage of oncology drugs demonstrably improved OS.

OS benefit often not investigated

To do this, they collected approval data including peer-reviewed literature from 2006 to 2023. Of the 392 approvals in total, only 87 (22%) were based on the investigation of OS; the remaining 305 oncology drugs (78%) were approved on the basis of surrogate parameters, 115 (29%) of which were accelerated approvals. The most commonly used endpoints for assessment were ORR (34 %) and PFS (26 %).

Of the oncology drugs approved on the basis of surrogate endpoints, half (153) were subsequently tested for their OS benefit, with only 29 (8 %) showing a positive result. Overall, only 125 of the 392 drugs examined (32%) were shown to have a proven overall survival advantage, while 267 (68%) had yet to demonstrate a survival benefit. Despite the sobering results, only 7% of the approved drugs were withdrawn from the market.

Deficits in drug approval

According to the study authors, the increasing use of surrogate parameters at the FDA may have expanded and accelerated the approval of oncology drugs – at the expense of efficacy. This is because the regulatory authorities tolerated a high degree of uncertainty for these products. This means that the regulatory authority is not fulfilling its mandate to bring safe and effective drugs to market. This also has an impact on other countries beyond the US, which often follow the decisions made there.

Their conclusion: higher standards are needed in drug approval to achieve the actual therapeutic goal of oncological treatments, a real increase in survival for seriously ill patients.