Dear readers,
The 2025 ASCO Annual Meeting in Chicago recently concluded with new data presented to help us better care for patients. Perhaps the most practice changing in prostate cancer, the AMPLITUDE trial highlighted a new role for PARP inhibitors (PARPi) in hormone sensitive disease!
We have been using PARPi in metastatic hormone resistant disease for years. Olaparib is FDA approved as monotherapy for the use in men with homologous recombination repair (HRR)-mutated disease (including BRCA, ATM, and other mutations), and in combination with abiraterone for patient with BRCA-mutated in front-line mCRPC (note: the study included mostly ARPI/ARSI naïve patients). The combination was based on the PROPEL study randomizing these patients to olaparib + abiraterone + prednisone versus abiraterone + prednisone + placebo. Overall survival was prolonged by 7 months and there were radiographic progression free survival benefits with a trend in all subgroups. However, the FDA chose to approve in BRCA patients alone due to benefits vs risks as the improvement was concentrated in this group.
TALAPRO-2 looked at the combination of enzalutamide and talazoparib versus enzalutamide in a similar patient population. ASCO 2025 updated these results. Radiographic progression free survival was improved in patients with HRR mutations (33.1 vs 19.5) months and OS was improved (45.8 vs 37.0 months). The benefit is enriched in patients with BRCA mutations. However, even in patients with HRR mutations that are not BRCA, there seemed to be benefit in the majority of mutations, including potentially a signal in ATM, a mutation that often does not show single gene benefit in many PARP trials. The hazard ratio for overall survival for ATM (though not powered to answer this specific question) was 0.7! There was a trend toward benefit with an all comer population, but the approval is only for patients with mCRPC with an HRR mutation.
Now, most exciting, is the new data from AMPLITUDE! This study randomized 696 men with mCSPC and HRR mutations to niraparib + abiraterone and prednisone versus placebo + abiraterone and prednisone (all patients had androgen deprivation therapy). Genes included with BRCA1/2, BRIP1, CDK12, FANCA, PALB2, RAD51B, and RAD54L. In patients with HRR mutations, hazard ratio for radiographic progression free survival is 0.63 (median not reached vs 29.5 months) and in patients with BRCA mutations (HR 0.52, NR vs 26 months). For first interim overall survival data analysis, hazard ration was 0.79 and for BRCA was 0.75. These data are statistically significant, but data is immature. Toxicity was as expected with a grade 3 anemia rate of 29% and a slight increase in hypertension with the 2 agents (grade 3 in 27%).
The data from AMPLITUDE seems practice changing! We will see what the FDA does. Do we need to wait for overall survival to spare toxicity for patients who will be on PARPi for years (concerns of fatigue, GI side effects, bone marrow issues) versus using in front line mCRPC? Only 36% of patients in the control arm received a PARPi, which is a criticism. However, we know patients with these mutations are at greater risk of aggressive disease. If the FDA approves this combination in mCSPC, I think offering PARPi up front would be a great option. And of course, we are waiting on data from TALAPRO-3 (talazoparib with enzalutamide in mHSPC) to learn more about data in this space.
Sincerely,
Drs. Benjamin Garmezy & Manojkumar Bupathi
