Results from the TALAPRO-2 trial shows talazoparib plus enzalutamide significantly extends life in men with HRR mutations.
Overall survival benefit is compelling enough to consider talazoparib and enzalutamide combination as standard first line therapy in patients with metastatic castration-resistant prostate cancer and mutations in the homologous recombination repair genes, particularly those with BRCA1 and BRCA2 gene mutations, researchers say.
Their findings from the final analysis from the TALAPRO-2 trial have been recently published in The Lancet.
Talazoparib plus enzalutamide combination significantly improved OS compared with enzalutamide plus placebo (HR 0·62 [95% CI 0·48–0·81, p=0.0005) in patients with HRR-deficient mCRPC. The median OS was 45.1 months with the combination versus 31.1 months with enzalutamide alone.
Professor Arun Azad, co-author of the study, and medical oncologist at Peter MacCallum Cancer Centre said the findings were important.
“The data from this trial shows that there’s a statistically significant and also clinically meaningful improvement in survival and quality of life for patients using this combination, as opposed to enzalutamide alone, which is the standard of care,” he said.
“This combination is a very effective new treatment option for patients with mCRPC and mutations in the HRR genes, which is about 25 percent of prostate cancer cases. That’s a large number of patients, who have more aggressive cancer and worse prognosis compared with those without HRR gene alterations.”
While the strongest data for using the combination is in HRR mutant patients, particularly those who’ve got BRCA mutations, it is a reasonable option for non-HRR mutant patients as well. The study shows radiographic progression-free survival continued to favour the combination in both cohorts.
In all-comers (cohort 1, unselected for HRR status), median OS increased from 37.0 to 45.8 months (HR 0.80; 95% CI 0.66–0.96; P = .0155) compared to enzalutamide plus placebo.
Professor Azad noted that the combination wouldn’t necessarily be used in all non-HRR mutant cases because it was important to recognise that there was toxicity of these drugs and the benefit must outweigh the toxicity.
The most common side-effect with this combination is anaemia, but it rarely leads to treatment cessation. In the study, only a very small percentage of patients needed to stop treatment. (Discontinuation rate due to adverse events was ~13%.).
“Anaemia usually occurs within the first three to four months and then the haemoglobin count starts to resolve,” said Professor Azad.
“Patients respond well to the interruption of treatment, dose reduction as well as use of blood transfusions. It is manageable, and it’s not impairing patient’s quality of life. If anything, in the long run, the quality of life ends up being better with longer disease control using this combination than with enzalutamide alone.”
The study calls for implementing routine HRR gene testing for all prostate cancer patients, especially those with metastatic disease.
“It’s really important that patients get tested and as physicians, we do more genetic testing in prostate cancer patients,” said Professor Azad.
“The infrastructure and technology are there, but the main barrier to testing is obtaining archival tissue samples and the associated cost of testing.
“If the PBS reimbursement for this combination would include all HRR mutated patients, for example, we can identify those mutations already from archival tumour tissue samples and could broaden the group of patients who benefit from the combination.
“It would be wonderful, if we are able to test the circulating tumour DNA (ctDNA) using liquid biopsies, to pick up these HRR alterations early for real-time evaluation of germline pathogenic variants as well as somatic mutations.”
He noted three major trials that might further support or refine the findings of TALAPRO 2.
The AMPLITUDE trial, which combines abiraterone plus niraparib, was showing positive results in hormone-sensitive prostate cancer patients with HRR gene alterations. It reported some initial data, at the American Society of Clinical Oncology conference this year, which demonstrated benefits to that combination over abiraterone alone.
The TALAPRO-3, which is very similar to TALAPRO-2, is investigating same drug combination – enzalutamide plus talazoparib versus enzalutamide. It is again in metastatic hormone-sensitive prostate cancer (mHSPC) with HRR gene alterations.
The EvoPAR study is an ongoing clinical trial, which is looking at these hormonal drugs plus another PARP inhibitor, saruparib, in metastatic castration-sensitive prostate cancer (mCSPC) patients, regardless of HRR gene alteration status.
“All those three studies are positive at some level. It’s quite possible that we’ll see the combination of a hormonal drug like enzalutamide plus a PARP inhibitor like talazoparib actually move forward into the mHSPC space, so it becomes part of the frontline management of patients with these HRR gene alterations,” said Professor Azad.
