Dana E. Rathkopf, MD, is a genitourinary medical oncologist and chair of the Research Council at Memorial Sloan Kettering Cancer Center in New York. 

Dana E. Rathkopf, MD, discusses the purpose of evaluating niraparib plus abiraterone acetate in metastatic castration-sensitive prostate cancer.

Dr Rathkopf on the Rationale for Evaluating Niraparib Plus Abiraterone Acetate in HRR+ mCSPC

“In the metastatic castration-resistant [prostate cancer] setting, the combination of niraparib plus abiraterone [acetate] demonstrated improvement in terms of radiographic progression-free survival, so we decided to [evaluate] this [combination] in [patients with] metastatic castration-sensitive prostate cancer in the phase 3 AMPLITUDE study.”

Dana E. Rathkopf, MD, a genitourinary medical oncologist and chair of the Research Council at Memorial Sloan Kettering Cancer Center, discussed the impetus and design of the phase 3 AMPLITUDE trial (NCT04497844), which evaluated the efficacy and safety of niraparib (Zejula) plus abiraterone acetate (Zytiga) for the treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC).

Data from the phase 3 study that demonstrated the efficacy of a PARP inhibitor combined with an androgen receptor pathway inhibitor (ARPI) in the mCSPC setting, Rathkopf began. She noted that patients with homologous recombination repair (HRR) mutations often have a worse prognosis. An effort toward identifying therapies—especially targeted therapies—is important to help improve outcomes for patients with prostate cancer, particularly those with metastatic castration-resistant prostate cancer (mCRPC), she explained. Previously, the combination of niraparib and abiraterone acetate demonstrated improvements in terms of radiographic progression-free survival (rPFS) in patients with mCRPC, she added. Therefore, investigators aimed to evaluate the respective regimen in patients with mCSPC in the phase 3 study, she asserted.

Of note, patients on the placebo-controlled, blinded study were randomly assigned to receive niraparib plus abiraterone acetate and androgen deprivation therapy (ADT; n = 348) or placebo plus abiraterone acetate and ADT (n = 348). Furthermore, patients included had mCSPC; an alteration in at least 1 HRR eligible gene, including 

; and an ECOG performance status of 0 to 2. Eligible patients were stratified based on prior docetaxel, volume of disease, and the type of HRR mutation, she noted. The primary end point was rPFS, she concluded.

Videos

Dr Rathkopf on Niraparib Plus Abiraterone Acetate and Prednisone in HRR+ mCSPC

“This is an important study for this patient population. This is a patient population [that] tends to have worse prognosis due to their HRR alteration status."

Dana E. Rathkopf, MD, a genitourinary medical oncologist and chair of the Research Council at Memorial Sloan Kettering Cancer Center, discussed the clinical significance of findings from the phase 3 AMPLITUDE trial (NCT04497844) of niraparib plus abiraterone acetate (Zytiga) and prednisone for patients with homologous recombination repair (HRR) gene–mutated metastatic castration-sensitive prostate cancer (mCSPC).

Findings from AMPLITUDE presented during the 

 revealed that patients with HRR-mutated mCSPC who received niraparib plus abiraterone acetate and prednisone (n = 348) achieved a median radiographic progression-free survival (rPFS) that was not evaluable compared with 29.5 months among patients who received placebo with abiraterone acetate and prednisone (n = 348; HR, 0.63; 95% CI, 0.49-0.80; 

 = .0001); these findings met the primary end point of the trial. Moreover, the addition of niraparib to abiraterone acetate and prednisone yielded a significant benefit in terms of time to symptomatic progression (TTSP; HR, 0.50; 95% CI, 0.36-0.69; 

Regarding safety, patients in the investigational arm experienced grade 3 or 4 treatment-emergent adverse effects (TEAEs) at a rate of 75%; 56% of these were treatment related. TEAEs leading to treatment discontinuation (15%), dose reduction (22%), and death (4%) were all reported.

These findings were significant for patients with HRR-mutated mCSPC because these patients tend to have a worsened prognosis due to their HRR mutational status, Rathkopf said. The option for a targeted regimen that includes the PARP inhibitor niraparib is key due to the improvement in rPFS and TTSP that it offers over standard of care approaches, she emphasized. Additionally, the regimen was well tolerated, she said. This approach offers patients an opportunity to do maximize their outcomes, Rathkopf concluded.

Dana E. Rathkopf, MD, discusses the clinical significance of findings from the phase 3 AMPLITUDE trial in HRR gene–mutated mCSPC.

Dr Rathkopf on the Efficacy of Niraparib Plus Abiraterone Acetate/Prednisone in HRR-Altered mCSPC

"After 30.8 months of median follow-up, radiographic progression-free survival favored the combination arm…and there was a 37% reduction in the [risk of progression or death in the] intention-to-treat population of [patients with] all HRR [gene] alterations that were tested in this study."

Dana E. Rathkopf, MD, a genitourinary medical oncologist and chair of the Research Council at Memorial Sloan Kettering Cancer Center, discussed efficacy results from the phase 3 AMPLITUDE trial (NCT04497844) of niraparib plus abiraterone acetate (Akeega) and prednisone for patients with homologous recombination repair (HRR) gene–mutated metastatic castration-sensitive prostate cancer (mCSPC).

Findings from the first and final analysis for radiographic progression-free survival (rPFS) and the first interim analysis for overall survival (OS) were presented at the 

 and showed that the study met its primary end point of rPFS, Rathkopf stated. After 30.8 months of median follow-up, rPFS favored the combination of niraparib and abiraterone acetate plus prednisone compared with abiraterone acetate and prednisone (AAP) alone, Rathkopf noted. Among patients with 

mutations, the combination arm demonstrated a 48% reduction in the risk of radiographic progression or death compared with AAP alone, with a median rPFS that was not estimable (NE) vs 26.0 months, respectively (HR, 0.52; 95% CI, 0.37-0.720; 

In the intention-to-treat population, which included all HRR gene alterations, the niraparib regimen resulted in a 37% reduction in the risk of radiographic progression or death compared with AAP alone, with a median rPFS that was NE vs 29.5 months, respectively (HR, 0.63; 95% CI, 0.49-0.80; 

 = .0001), Rathkopf noted. This rPFS benefit was generally consistent across predefined subgroups.

Furthermore, the niraparib regimen significantly reduced the risk of symptomatic progression vs AAP by 56% in the 

-mutant subgroup (HR, 0.44; 95% CI, 0.29-0.68; 

 = .0001) and by 50% in the overall HRR gene–mutant population (HR, 0.50; 95% CI, 0.36-0.69; 

Regarding OS, the first interim analysis demonstrated a numerical, though not statistically significant, reduction in the risk of death with the niraparib regimen vs AAP: 25% in the 

-mutant subgroup (HR, 0.75; 95% CI, 0.51-1.11; 

 = .15) and 21% in the HRR gene–mutant population (HR, 0.79; 95% CI, 0.59-1.04; 

These findings support the potential role of niraparib plus abiraterone acetate and prednisone in delaying disease progression in patients with HRR gene–mutated mCSPC, Rathkopf concluded.

Dana E. Rathkopf, MD, discusses the efficacy of niraparib plus abiraterone acetate and prednisone in patients with mCSPC and HRR gene alterations.

Dana E. Rathkopf, MD, Memorial Sloan Kettering Cancer Center, discusses the emergence of the androgen receptor splice variant-7 (AR-V7) biomarker in the treatment of patients with prostate cancer.

AR-V7 has been previously studied in circulating tumor cells in men with castration-resistant prostate cancer to identify primary resistance to enzalutamide (Xtandi) and abiraterone acetate (Zytiga) therapy.

AR-V7 is currently being looked at as a biomarker to find an appropriate patient population, wherein physicians then may be able to use combinations of other drugs to overcome resistance to targeted therapy.

According to Rathkopf, biomarkers like this are the key to understanding and mitigating resistance in prostate cancer.

Dr. Rathkopf on AR-V7 Biomarker in Prostate Cancer

Dana E. Rathkopf, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses agents being explored as treatments for patients with prostate cancer, including apalutamide and PARP inhibitors.

Apalutamide, a non-steroidal antiandrogen agent, is different from abiraterone acetate (Zytiga) and enzalutamide (Xtandi), as it has not yet been approved for regular use. The agent has shown efficacy in phase I and II studies, and there are several ongoing phase III registration studies looking at the drug. However, since it is not FDA approved, it is not yet available for everyday patients who are not on clinical trials. The pressing question Rathkopf asks is, "Can this drug get approved in this space to make it available for patients in need?"

There is also ongoing work being done regarding PARP inhibition in prostate cancer. One study that was recently completed by Maha Hussain, MD explored the combination of a PARP inhibitor plus abiraterone. Then, another ongoing study is investigating abiraterone plus a PARP inhibitor. Additionally, researchers will be stratifying results based on DNA-repair deficits, Rathkopf says. Results from these trials are highly anticipated amongst the community, she adds.

Dr. Rathkopf on Investigative Agents in Prostate Cancer

Dana E. Rathkopf, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, discusses mitigating androgen receptor (AR)-resistance in patients with prostate cancer.

AR is a very important target for prostate cancer, Rathkopf explains. Additonally, AR-targeted agents have only been available for patients with prostate cancer for about 5 years. Researchers in the field are now trying to catch up and determine which patients are best candidates to receive AR-targeted therapy, as well as working to identify what the mechanisms of resistance are and if combinations with chemotherapy, immunotherapy, or DNA mismatch-repair agents will improve outcomes.

There are phase III studies ongoing in this space that have completed accrual. One is an ALLIANCE study exploring the AR-targeted agent enzalutamide (Xtandi) versus enzalutamide plus abiraterone acetate (Zytiga; NCT01949337). There is also another phase III that is comparing abiraterone with or without apalutamide, which is a second-generation AR-directed agent. Both studies are highly anticipated in the field, Rathkopf concludes.

Dana E. Rathkopf, MD

Articles

Dr Rathkopf on the Rationale for Evaluating Niraparib Plus Abiraterone Acetate in HRR+ mCSPC

Dr Rathkopf on Niraparib Plus Abiraterone Acetate and Prednisone in HRR+ mCSPC

Dr Rathkopf on the Efficacy of Niraparib Plus Abiraterone Acetate/Prednisone in HRR-Altered mCSPC

Dr. Rathkopf on AR-V7 Biomarker in Prostate Cancer

Dr. Rathkopf on Investigative Agents in Prostate Cancer

Dr. Rathkopf on Mitigating AR-Resistance in Prostate Cancer