Talazoparib regimen improves outcomes among certain men with metastatic prostate cancer
SAN FRANCISCO — The addition of talazoparib to first-line enzalutamide extended imaging-based PFS among men with metastatic castration-resistant prostate cancer, according to results of the randomized phase 3 TALAPRO-2 study.
The regimen — which also delayed worsening in global health status and quality of life — conferred benefit regardless of homologous recombination repair (HRR) status, findings presented at ASCO Genitourinary Cancers Symposium showed.
“We saw a statistically significant and clinically meaningful improvement in radiographic progression-free survival, not only among HRR-deficient patients but also in HRR-nondeficient patients, and also by prospective tumor tissue testing,” Neeraj Agarwal, MD, presidential endowed chair of cancer research and director of the genitourinary oncology program at Huntsman Cancer Institute at University of Utah, told Healio. “There is no question about the efficacy of this combination.”
Despite therapeutic advances in the past decade, metastatic castration-resistant prostate cancer remains lethal and more effective treatments are needed, Agarwal said.
Enzalutamide (Xtandi; Astellas, Pfizer), a potent androgen receptor signaling inhibitor, is the standard treatment in this setting.
Researchers hypothesized that the combination of an androgen receptor signaling inhibitor and poly(ADP-ribose) polymerase (PARP) inhibitor may extend the efficacy of PARP inhibitors to men with prostate cancer whose tumors do not have homologous recombination repair (HRR) gene alterations.
In TALAPRO-2, Agarwal and colleagues assessed the combination of the PARP inhibitor talazoparib (Talzenna, Pfizer) and enzalutamide. Talazoparib is approved in the U.S. for treatment of certain patients with locally advanced or metastatic BRCA-positive, HER2-negative breast cancer.
TALAPRO-2 included 805 men with mildly symptomatic or asymptomatic metastatic castration-resistant prostate cancer unselected for genetic alterations in DNA damage repair pathways.
All men had ECOG performance status 0 or 1, were receiving ongoing androgen deprivation therapy and had received no prior life-prolonging therapy for castration-resistant prostate cancer.
Researchers assigned 402 men to first-line therapy with 0.5 mg talazoparib plus 160 mg enzalutamide daily. The other 403 received placebo plus enzalutamide.
The talazoparib and placebo groups appeared well-balanced for baseline demographics and disease characteristics.
Radiographic PFS assessed by blinded independent committee review served as the primary endpoint.
Median follow-up was 24.9 months in the talazoparib group and 24.6 months in the placebo group.
Results showed significantly longer radiographic PFS among men assigned talazoparib-enzalutamide (not reached vs. 21.9 months; HR = 0.63; 95% CI, 0.51-0.78). The benefit persisted in subgroup analyses based on age, ECOG performance status, Gleason score, site of metastasis and other variables.
Researchers observed the benefit among those with HRR-deficient disease (HR = 0.46; 95% CI, 0.3-0.7), those with HRR-non-deficient disease or unknown HRR status (HR = 0.7; 95% CI, 0.54-0.89), and those with confirmed HRR-nondeficient disease by prospective tumor tissue testing (HR = 0.66; 95% CI, 0.49-0.91).
OS data remained immature. An interim analysis showed improved OS in the talazoparib group but the difference had not reached statistical significance (HR = 0.89; 95% CI, 0.69-1.14).
Other efficacy measures — including objective response rate (61.7% vs. 43.9%), complete response (37.5% vs. 18.2%), PSA response greater than 50%, time to PSA progression (median, 26.7 months vs. 17.5 months; HR = 0.72; 95% CI, 0.58-0.89), and time to cytotoxic chemotherapy (HR = 0.49; 95% CI, 0.38-0.65) — significantly favored the combination regimen.
A member of the audience asked if improved radiographic PFS in absence of an OS benefit is sufficient to “declare victory.”
“If I can delay chemotherapy, if I can delay deterioration in quality of life, and I can delay progression or death on next therapy, I think those are meaningful endpoints, and I think those endpoints will be meaningful to my patients,” Agarwal said. “Even without an overall survival benefit, these drugs remain relevant in my clinic if my patient wants to have them.”
Researchers observed no new safety signals and characterized toxicity as generally manageable.
A higher percentage of men assigned talazoparib-enzalutamide experienced grade 3/grade 4 treatment-emergent adverse events (71.9% vs. 40.6%).
The most common grade 3/grade 4 treatment-emergent adverse events among men treated with talazoparib included anemia (65.8%), neutropenia (35.7%), fatigue (33.7%) and thrombocytopenia (24.6%). The most common among men assigned placebo included fatigue (29.4%), back pain (18%) and anemia (17.5%).
Notably, 49% of men assigned talazoparib had grade 1 or grade 2 anemia at baseline, Agarwal said. Median time to onset of grade 3 or grade 4 anemia was 3.3 months, and those men were managed with dose reductions.
“Only 8.3% discontinued talazoparib due to anemia, and the median relative dose intensity of talazoparib remained above 80%,” Agarwal said.
Investigators reported pulmonary embolism among 10 men (2.5%) assigned talazoparib and three (0.7%) in the placebo group. All but one case in the talazoparib group was grade 3.
A higher percentage of men assigned talazoparib required dose interruptions (75.4% vs. 23.4%) or dose reductions (56% vs. 7.2%). Treatment-emergent adverse events led to discontinuation for 19.1% of those assigned talazoparib and 12.2% of those assigned placebo.
Researchers reported 13 grade 5 treatment-emergent adverse events in the talazoparib group — none of which were treatment related — and 18 in the placebo group, two of which were deemed related to treatment.
Investigators reported longer median time to definitive clinically meaningful deterioration of global health status/quality of life among men assigned talazoparib (30.8 months vs. 25 months; HR = 0.78; 95% CI, 0.62-0.99).
The results of TALAPRO-2 support the use of talazoparib plus enzalutamide as first-line treatment for men with metastatic castration-resistant prostate cancer regardless of HRR gene alteration status, Agarwal said.
“The magnitude of benefit was always expected to be higher for selected patients vs. patients who do not have mutations, but I was not surprised to see the benefit among all patients,” Agarwal told Healio. “Obviously we have to wait for the regulatory bodies’ approval but, if this is available, I will offer it to my patients and they will decide whether they want to get this treatment.”
Perspective
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The TALAPRO-2 results represent an intriguing finding for men with metastatic castration-resistant prostate cancer, particularly in conjunction with the previously reported PROPEL study results. However, given that many patients receive an androgen receptor inhibitor now for metastatic castration-resistant prostate cancer, these results are less relevant to current practice. Demonstration of an OS benefit of the combination would be optimal to change standard of care vs. potential sequential therapy.
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Agarwal N, et al. Abstract LBA17. Presented at: ASCO Genitourinary Cancers Symposium; Feb. 16-18, 2023; San Francisco.