HARMONY Study Aims to Personalize PARP Inhibition in mHSPC Through Adaptive Design, Diverse Patient Enrollment

Qian (Janie) Qin, MD

In an interview with OncLive®, Qian (Janie) Qin, MD, highlighted the importance of early somatic and germline testing to inform subsequent treatment decisions for patients who with metastatic hormone-sensistive prostate cancer (mHSPC) who develop metastatic castration-resistant prostate cancer (mCRPC); reviewed pivotal trials supporting PARP inhibitor monotherapy and combinations across disease settings; and emphasized the adaptive design and intentional focus on enrolling non-Hispanic Black and Hispanic/Latino patients with mHSPC in the phase 2 HARMONY study (NCT06392841).

“Getting somatic testing and hereditary testing in the hormone-sensitive setting allows me to plan [ahead] for the first-line mCRPC setting, because it does take 2 to 3 weeks for those results to come back,” Qin expanded.

In a concurrent article, Qin also discussed the use of radioligand therapy in mCRPC, including key considerations when applying data from the phase 3 PEACE-3 trial (NCT02194842) in current practice and new and emerging radioligand therapies that could change the mCRPC treatment landscape.

Qin is an assistant professor in the Department of Internal Medicine at UT Southwestern Medical Center and the Eugene P. Frenkel, MD Scholar in Clinical Medicine at Harold C. Simmons Comprehensive Cancer Center in Dallas, Texas.

OncLive: What role does molecular testing have in your clinical practice, and do you find that you have the sequencing results in time to inform treatment decisions in mCRPC?

Qin: Molecular testing is so important these days, as PARP inhibitors [continue to move] from later lines to first-line mCRPC. I tend to [have] somatic and hereditary testing [performed for] all patients who walk [into] my clinic, because the majority of them have metastatic disease or high-risk locoregional disease, both of which are indications for homologous recombination repair [HRR] testing. That allows me to have the results in time, because that’s not currently the standard [practice] in the mHSPC setting.

That’s my clinical practice, so that at the time of progression, I have everything we need to make the best decision for first-line mCRPC.

What are some of the pivotal studies supporting PARP inhibitor monotherapy/combination regimens in mCRPC?

The prior [phase 3] trials for monotherapy [include the] PROfound trial [NCT02987543] with olaparib [Lynparza] in an all-comer [population with] HRR alterations. Then we have the TRITON-3 trial [NCT02975934] with rucaparib [Rubraca] for patients with BRCA1/2 and ATM [mutations]. [Lastly], we have the [phase 3] PROpel [NCT03732820], MAGNITUDE [NCT03748641], and TALAPRO-2 [(NCT03395197) trials] for combination regimens; these are all in the mCRPC setting.

There are also [the phase 3 trials evaluating] PARP inhibition in the first-line mHSPC setting. [These include] AMPLITUDE [(NCT04497844), which evaluated] niraparib [Zejula] plus abiraterone acetate [Zytiga]/prednisone vs abiraterone acetate/prednisone [alone]; and TALAPRO-3 [(NCT04821622), which assessed] talazoparib [Talzenna] plus enzalutamide [Xtandi] vs enzalutamide.

What makes the phase 2 HARMONY study unique relative to these prior trials?

The HARMONY trial is in the mHSPC setting. It is more of an adaptive trial that also allows patient to have a choice [of treatment] based on their prostate-specific antigen [PSA] response.

The trial design is somewhat similar to AMPLITUDE, in that we're also using niraparib plus abiraterone acetate [and prednisone]. [The trial is evaluating] androgen deprivation therapy plus niraparib, but the patients are treated for 24 weeks.

For patients who didn’t have a very good PSA response—where their PSA remains greater than 4 ng/mL but is not progressive—the patients have the choice to continue on the triplet, or drop the niraparib and do a triplet with ADT plus abiraterone plus docetaxel. [It is] somewhat of an escalation in their therapy. For patients who had PSA less than or equal to 4 ng/mL, they will continue on the niraparib triplet for a total of 1 year.

At the 1-year mark, patients again have a choice. If their PSA [decreased] to less than 0.2 ng/mL, they can continue treatment, or they can stop therapy. That is somewhat of a de-escalation [of therapy]. Patients whose PSA level is greater than or equal to 0.2 ng/mL will continue that triplet until progression or unacceptable toxicity, for up to 2 years.

We know that in the landmark phase 3 trials that have led to approval of our current standard-of-care therapies, the enrollment of racial and ethnic minorities is unfortunately very small. The African American patient population usually represents less than 3% to 5% of the enrolled patients; Hispanic/Latino patients usually [represent] less than 10% to 15% [of the total population on clinical trials]. [Therefore, the HARMONY] trial is focused on the enrollment of non-Hispanic, Black patients and Hispanic/Latino patients, so that we can better understand their HRR alterations and their response to therapy, as well as their toxicity.