Prostate cancer cells

The U.S Food and Drug Administration (FDA) has approved a new drug combination for men with metastatic, castration-resistant prostate cancer (mCRPC) and certain DNA repair gene mutations, widening treatment options for this large patient population.

The androgen-receptor inhibitor enzalutamide plus the PARP inhibitor talazoparib can now be used as first-line treatment for mCRPC patients who have homologous recombination repair (HRR) gene alterations.

It marks the second FDA approval for a PARP inhibitor in prostate cancer this month. Olaparib combined with the hormone therapy abiraterone and corticosteroid treatment was given the green light earlier for mCRPC patients with tumors that have BRCA gene mutations.

Crucially, however, this latest approval is open to more patients. While BRCA mutations are present in approximately 10% of mCRPC patients, around a quarter have the wider DNA repair mutations covered by the latest FDA nod.

Regulatory approval for enzalutamide/talazoparib was based on results from TALAPRO-2—a multicenter, Phase III trial of more than 800 patients published recently in The Lancet.

The study met its primary endpoint of radiographic progression-free survival, with a 55% reduction in the risk of disease progression or death when enzalutamide was used in combination with talazoparib instead of placebo.

There were also clinically meaningful improvements in a variety of other outcomes, with delays in chemotherapy, progression in prostate specific antigen (PSA), and deterioration in quality of life.

“To have a drug combination that will significantly improve all these outcomes in a statistically significant and clinically meaningful fashion is great news for our patients,” said lead TALAPRO-2 author Neeraj Agarwal, PhD, presidential endowed chair of cancer research at the Huntsman Cancer Institute of the University of Utah.

He highlighted the 17-month delay in progression of PSA levels shown with active combination treatment.

“PSA progression means a lot to the patients, and just by adding talazoparib you are delaying PSA progression from 11 months to 28 months. This is striking, these are striking results.”

Enzalutamide is already one of the most commonly used medications in patients with mCRPC. It is an oral, second-generation androgen-receptor inhibitor that works by blocking the interaction of testosterone at the androgen receptor.

Talazoparib is an oral inhibitor of the DNA repair enzyme PARP that renders rapidly dividing cancer cells particularly susceptible to DNA damage, thereby affecting their survival.

The rigorous design of TALAPRO-2 meant that every participant had prospective tumor tissue testing for HRR gene alternations. This was not performed in the major prostate-cancer PROpel trial, whose subgroup analysis informed the FDA’s olaparib combination approval.

HRR status was also a stratification factor in TALAPRO-2 when they randomized patients, so each arm had similar numbers of particular cases.

“There is no doubt that all regulatory bodies in the world will approve this combination for the indication which has been chosen by the FDA, for sure,” said Agarwal, noting the HRR patient restrictions under the current approval.

“But then some regulatory bodies can go beyond and say: ‘Hey guys you showed improved outcomes in all patients so we are going to give you approval for all patients.’”

While the trial was not designed to assess overall survival so quickly, there was also a strong trend for overall survival benefit, and Agarwal is optimistic this will continue.

‘I am really hoping, looking at the trends, that we will hit the overall survival mark at the time of next analysis, which should be happening quite soon, hopefully later this year or early next year.’

He also pointed out the benefits seen in patients who were not positive for HRR gene mutations.

‘I think the next key thing is to find out what is the mechanism of action behind the responsiveness in those patients. Because I think once we find out, once we identify who among those negative patients seem to be responding, we will expand the patient population who will benefit from the combination,” he said.

Simon Chowdhury, PhD, a clinical researcher from the U.K’s medical research council who has been involved in prostate cancer studies such as STAMPEDE and TITAN, welcomed the FDA’s approval.

“This has the potential to be a step change in treatment,” he said. “We need to understand how best to identify which patients benefit most.

“For HRR not all genes are equal, not all mutations are equal and not all testing is equal.”

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