For some men with metastatic prostate cancer, the diagnosis is accompanied by a double threat: that of the disease itself, but also that of genetic anomalies which accelerate its progression. Presented at the ASCO World Congress in Chicago, the results of the international TALAPRO-3 trial open a major perspective. For the first time, a personalized medicine strategy used from the start of treatment makes it possible to very significantly delay the progression of the disease in the patients most at risk.
Behind the same diagnosis, cancers which do not all have the same aggressiveness
Every year, nearly 50,000 men learn that they have prostate cancer in France. Although therapeutic advances have considerably improved their treatment, certain forms of the disease remain particularly formidable.
This is particularly the case when tumor cells present certain abnormalities affecting genes involved in DNA repair, such as BRCA1, BRCA2, ATM, ATR, CDK12 or even CHEK2. These genetic alterations promote the accumulation of errors in the genetic material of cancer cells and are often associated with more aggressive disease, more difficult to control and a less favorable prognosis.
For a long time, these patients received the same treatments as others. But the precision medicine revolution is gradually changing the situation.
The idea is simple: rather than treating only the diseased organ, it is also a matter of targeting the biological weaknesses specific to each tumor.
This is precisely the ambition of the TALAPRO-3 trial, presented at the annual meeting of the American Society of Clinical Oncology (ASCO) and published simultaneously in the prestigious New England Journal of Medicine.
A double-barrel strategy to deprive the tumor of its weapons
Coordinated by Professor Karim Fizazi, medical oncologist and general director of the Oscar Lambret Center, the study included nearly 600 patients with hormone-sensitive metastatic prostate cancer presenting an alteration of DNA repair genes. Participants were randomly assigned to two groups.
All received standard-of-care hormone therapy aimed at depriving the tumor of the hormones that fuel its growth. Added to this was enzalutamide, a new generation treatment that blocks hormonal signals more effectively.
The real innovation lay in the addition of talazoparib for half of the patients.
This medication belongs to the PARP inhibitor family. Its role is to prevent cancer cells from repairing the damage that accumulates in their DNA. Already weakened by their genetic anomalies, they then find themselves deprived of their ultimate survival mechanism.
Researchers thus sought to exploit a vulnerability specific to tumors carrying BRCA mutations and other related abnormalities.
The results exceed expectations:
- After a median follow-up of more than three years, the talazoparib-enzalutamide combination reduced the risk of radiological disease progression or death by 52% compared to standard treatment;
- Three years after the start of treatment, 77% of patients in the combination group had still not shown progression, compared to 56% in the control group.
- Even more impressive, in patients with a BRCA1 or BRCA2 mutation, the risk of progression or death was reduced by approximately 63% compared to standard treatment;
- The analyzes presented at ASCO show that patients with a BRCA2 alteration are among those who benefit the most from this strategy.
A breakthrough that could reshape treatment standards
Beyond the figures, it is perhaps the moment when this treatment occurs which marks the real break. Until now, PARP inhibitors were mainly used when the disease had become resistant to conventional hormonal treatments. TALAPRO-3 suggests that acting earlier could permanently delay the progression of cancer.
The first overall survival data point in the same direction. After forty months of follow-up, the researchers observed a 23% reduction in the risk of death, even if these results still remain preliminary and require further observation.
For Professor Karim Fizazi, coordinator of the study, the importance of these results is considerable:
“These clinical results are exceptional. For patients suffering from hormone-sensitive metastatic prostate cancer and presenting an alteration of the BRCA2 gene, the talazoparib / enzalutamide combination can considerably delay the progression of the disease while preserving their quality of life. This is a major step forward for personalized medicine in genitourinary oncology”.
The researchers also emphasize that the quality of life reported by the patients remained generally preserved despite the intensification of treatment. The adverse effects observed were mainly hematological, including anemia, a known effect of PARP inhibitors.
An essential question now remains: identifying patients likely to benefit from it early enough. Because this advance reinforces more than ever the need to generalize genomic tests in men with metastatic prostate cancer.
The future of treatment no longer rests solely on the location of the tumor or its stage of development. It also depends on its genetic identity. And it is precisely this finer understanding of the disease that today allows us to glimpse progress that we thought was still out of reach a few years ago.