A trio of new pivotal trial entries

This week has been particularly interesting in terms of new phase 3 trials posted on the clinicaltrials.gov registry, and three new studies stand out in particular, given that they indicate the speed at which the assets are progressing through development.

Lagging behind in a highly competitive field, Lilly is stepping on the gas for its KRAS G12C inhibitor LY3537982, moving straight from phase 1 to 3, for instance, while Amgen's DLL3-targeted T-cell engager tarlatamab is now moving into earlier lines in SCLC. Perhaps most noteworthy is AstraZeneca's first phase 3 study of saruparib, coming just three years after this selective PARP1 inhibitor first entered the clinic. 

AstraZeneca is now kicking off the Evopar-Prostate01 trial. Saruparib will be evaluated in combination with physician's choice of new hormonal agent (NHA), meaning Zytiga, Nubeqa or Xtandi, versus placebo and NHA in 1,800 patients with metastatic castration-sensitive prostate cancer.

This trial includes two cohorts based on HRR-mutation status; 550 patients will be assigned to the HRR-mutant cohort and 1,250 to the non-HRRm arm. Astra claims that the selective inhibition of PARP1 addresses the haematological adverse event profile of first-generation PARP1/2 inhibitors, leading to an improved therapeutic index and importantly the possibility to combine with other agents. 

Moving fast

Lilly too is moving fast with the KRAS G12C inhibitor LY3537982, moving from phase 1 straight into phase 3. The Sunray-01 trial aims to position the asset in first-line advanced NSCLC with the particular feature that the trial will be competing for a piece of the KRAS G12C-mutation pie against Amgen's Lumakras and Mirati's Krazati in their respective phase 3 trials. 

The trial is to start recruiting 1,016 patients early next year. Its first part will evaluate the combination of LY3537982 and Keytruda versus Keytruda alone in patients with PD-L1 expression ≥50%, while part B will focus on LY3537982 plus Keytruda and chemotherapy versus the Keytruda regimen alone in patients regardless of PD-L1 expression. 

Amgen's Codebreak-202 trial, initiated in June 2023, is looking at a Lumakras platinum doublet versus the Keytruda platinum doublet in non-squamous PD-L1-negative NSCLC patients. Mirati's Krystal-7 trial is expected to start enrolling into its phase 3 portion by the end of the year and, after a change in strategy, will evaluate the combination of Krazati and Keytruda in patients with high PD-L1 expression. 

Finally, of particular interest is the phase 3 Dellphi-306 trial of Amgen's DLL3-targeted T-cell engager tarlatamab, which is now moving into early lines in SCLC. The study will evaluate tarlatamab versus placebo in 400 limited-stage SCLC patients who have not progressed following concurrent chemoradiotherapy. 

This is the second phase 3 trial to kick off for tarlatamab, though Amgen has also revealed its intention to start a third phase 3 in the next 6-8 months. This upcoming trial will evaluate tarlatamab as front-line induction and maintenance therapy in extensive-stage SCLC patients, representing the biggest market opportunity for the first-in-class asset.

Phase 3 trials summary:

Note: i) NHA=new hormonal agents (Zytiga, Xtandi, Nubeqa). ii) HRRm=homologous recombination repair mutation. Source: clinicaltrials.gov.