Presented here are summaries of three abstracts from the 2023 ASCO Annual Meeting that are pertinent for patients with metastatic castration-resistant prostate cancer. The first two focus on men with homologous recombinant repair (HRR) gene alterations, including BRCA1/2. In the first study, BRCA1/2 alterations were found to be associated with worse outcomes in metastatic castration-resistant prostate cancer than non-BRCA and other HRR alterations. A second study found the combination of the PARP inhibitor talazoparib plus the androgen receptor blocker enzalutamide improved outcomes in HRR-mutated metastatic castration-resistant prostate cancer, particularly those with BRCA1/2 alterations. The third study showed that treatment with radium-223 did not impact a patient’s chances of going on to subsequent life-prolonging therapy.
BRCA Mutations and Survival
Patients with HRR-deficient mutations and metastatic castration-resistant prostate cancer who also harbored BRCA alterations experienced worse survival outcomes than did patients who did not have BRCA alterations and those with non-BRCA HRR mutations, according to an analysis from the CAPTURE trial.1
Patients with BRCA variants (both somatic and germline) had significantly worse radiographic progression–free survival, time to second objective disease progression, and overall survival compared with the total non–BRCA-mutated population. Patients with these BRCA alterations also had worse second objective disease progression and overall survival vs patients whose disease harbored other HRR mutations but were BRCA wild-type.
David Olmos, MD, PhD
“These results further support the importance of screening for germline and somatic BRCA1/2 alterations to deliver more precise care for our patients, especially in light of phase III trials that suggest poor outcomes for patients with BRCA alterations,” stated presenting author David Olmos, MD, PhD, of Hospital Universitario 12 de Octubre in Madrid. “Poor outcomes with other HRR [deficiencies] may be averted by adding a PARP inhibitor.”
Cohort 1 of the CAPTURE trial, part of the PROCURE biomarker study platform, pooled the populations with metastatic castration-resistant prostate cancer enrolled in four separate trials: PROREPAIR-B, PROSENZA, PROSTAC, and PROSABI. They were evaluated in a custom next-generation sequencing panel with paired somatic or germline DNA analysis for HRR mutations in BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B, and RAD54L. Patients were classified as HRR-deficient if they had mutations in at least one allele of at least one gene.
The patients either received novel hormonal therapy (60.4%) or a taxane (39.6%) as first-line treatment of metastatic castration-resistant prostate cancer, including docetaxel, cabazitaxel, abiraterone acetate, and enzalutamide. More than 80% went on to receive second-line treatment after disease progression.
A total of 729 patients on the trials volunteered to undergo genomic analysis and were classified as BRCA1/2, HRR non-BRCA, and non-HRR. They were also classified by germline, somatic, or none as well as biallelic, monoallelic, or none. Of the patients, 223 (30.6%) had HRR mutations, 96 (13.2%) had BRCA variants, and 127 (17.4%) had HRR non-BRCA alterations. A total of 25 patients (3.4%) had germline BRCA alterations, and 71 (9.8%) had somatic BRCA alterations. Of the HRR non-BRCA alterations, the most common were ATM in 64 patients (8.8%) and FANCA in 38 patients (5.2%).
No association was identified between the choice of first-line treatment and BRCA or HRR status. However, a greater percentage of patients with BRCA or HRR status had additional therapy compared with less than 80% of patients classified in the other subgroups.
“We may conclude that BRCA patients have significantly worse outcomes than patients with mutations in HRR non-BRCA, and those with alterations in HRR non-BRCA genes have worse outcomes than nonmutated patients,” Dr. Olmos told listeners.
PARP Inhibitor Plus Enzalutamide
Combining talazoparib and enzalutamide significantly prolonged radiographic progression-free survival as first-line therapy for patients with metastatic castration-resistant prostate cancer harboring HRR gene alterations.2 The improvement was both statistically significant and clinically meaningful, according to investigators of the TALAPRO-2 study.
TALAPRO-2 is the first phase III study to compare the combination of the PARP inhibitor talazoparib plus enzalutamide (n = 200) vs placebo and enzalutamide (n = 199) in metastatic castration-resistant prostate cancer. Results of the study were presented at the 2023 ASCO Annual Meeting and published in TheLancet Oncology to coincide with the presentation.2,3
The randomized, double-blind TALAPRO-2 study found that the combination of talazoparib at 0.5 mg/d plus enzalutamide at 160 mg/d as first-line therapy reduced the risk of radiographic progression–free survival in the overall study population by 55% compared with placebo plus enzalutamide at 160 mg/d. Median follow-up was about 17 months. Median radiographic progression–free survival was not reached in the talazoparib arm vs 13.8 months (95% confidence interval = 11.0–16.7 months) in the placebo arm (P < .0001).
The combination improved radiographic progression–free survival in all subgroups of HRR-deficient patients enrolled on the trial, most notably for patients with BRCA alterations. In the overall study population, patients with BRCA alterations experienced an 80% reduction in radiographic progression–free survival compared with non–BRCA-mutated patients (P < .0001). Patients on the combination arm with BRCA alterations had a 32% reduction in radiographic progression–free survival vs patients with other mismatch-repair gene alterations on the combination arm (P = .06).
“Based on these data, I believe that talazoparib plus enzalutamide, if approved, should become a standard of care for patients with metastatic castration-resistant prostate cancer HRR alterations [and] mainly those with BRCA alterations,” stated Karim Fizazi, MD, PhD, Professor of Oncology at the University of Paris-Saclay and Gustave Roussy.
Karim Fizazi, MD, PhD
The study had two cohorts: cohort 1 included all comers (n = 805), and cohort 2 included those with HRR mutations alone (n = 399). At baseline, BRCA2 alterations were present in 31% of patients on the combination arm compared with 36.7% on the placebo arm, whereas BRCA1 alterations were present in about 6% of patients on both arms. HRR-deficient patients with only a BRCA2 alteration on the combination arm still had a significant radiographic progression–free survival benefit compared with BRCA2 patients on the placebo arm (P < .0001). Similar results were seen with patients who had a BRCA1 alteration alone (P = .074), and a significant radiographic progression–free survival benefit was seen in patients with a BRCA cluster in their disease (P < .0001).
For all comers in both arms, about 38% of patients had prior abiraterone or docetaxel. Metastases to the bone were present in 87.5% of the talazoparib arm and 79.4% of the placebo arm. The median prostate-specific antigen (PSA) level was about 18.5 ng/mL in both arms.
An interim analysis of overall survival in the HRR-deficient cohort found that the combination reduced the risk of death by 31% (P = .068). Median overall survival was not reached in the combination arm and was 33.7 months in the placebo arm. “Survival data are still immature,” Dr. Fizazi noted.
The combination of talazoparib and enzalutamide in the first-line setting also prolonged the time to PSA progression, reducing the risk of disease progression by about 60%. Median time to PSA progression was 28.6 months with the combination vs 11.1 months with the placebo (P < .0001).
Objective response rates were 67.1% for the combination vs 40% for the placebo. Complete response rates were 38.4% vs 18.5%, respectively. Stable disease was present in 32.3% vs 20%, respectively.
No new safety signals were reported in the combination arm. There were more grade 3 or 4 treatment-emergent adverse effects in the combination arm than in the placebo arm: 66.2% vs 37.2%, respectively. However, treatment discontinuation rates were comparable in both arms: 10.1% vs 7%, respectively. The rate of adverse events of interest remained low with talazoparib, with no reported cases of myelodysplastic syndrome or acute myeloid leukemia. Time to clinically meaningful deterioration of quality of life was prolonged in the combination arm: median of 27.1 months vs 19.3 months in the placebo arm (P = .032).
Based on these results, on June 20, 2023, the U.S. Food and Drug Administration approved the combination of talazoparib plus enzalutamide as first-line treatment for HRR-deficient metastatic castration-resistant prostate cancer.
Use of Radium-223
Radium-223 was safe and did not prevent patients with metastatic castration-resistant prostate cancer from receiving further life-extending therapies, including chemotherapy, according to an interim analysis of the observational REASSURE trial.4
“Most patients completed five to six injections of radium-223, with no new safety signals reported. In addition, treatment with radium-223 resulted in an overall survival of approximately 18 months in patients with metastatic castration-resistant prostate cancer,” said Daniel Y. Song, MD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore.
The analysis of the prospective, single-arm, observational study included a cohort of patients (n = 498) from the United States with confirmed metastatic castration-resistant prostate cancer and bone metastasis scheduled to receive treatment with radium-223 and received at least one dose. Median patient age was 74 years, and median duration of observation was 11.9 months at data cutoff.
Most patients (81%) had bone-only metastases. More than two-thirds of patients (69%) received five or six injections of radium-223. About half (51%) received radium-223 with another life-prolonging therapy, with enzalutamide being the most frequent partner.
Prior chemotherapy was associated with a greater need for therapeutic or preventive treatments for bone marrow suppression. A total of 37% of patients who received prior chemotherapy and 16% of patients who did not receive prior chemotherapy required either therapeutic or preventive treatment for bone marrow suppression.
More than half the patients (58%) in this analysis who reported a Brief Pain Inventory (Short Form) score of 2 or higher at baseline had a clinically meaningful pain response during treatment.
The safety of radium-223 was consistent with known side effects. No new safety signals were reported. Treatment-emergent serious adverse effects were reported in 21% of patients, and drug-related serious adverse events were observed in 6% of patients.
During follow-up, 60% of patients died, and the median overall survival was 17.8 months. These results compare favorably with those from the ALSYMPCA trial (median overall survival of 14.9 months).
DISCLOSURE: Dr. Olmos has received institutional honoraria from Astellas, Pharma, Bayer, and Janssen; has served as a consultant or advisor to AstraZeneca, Bayer, Clovis Oncology, Daiichi Sankyo, Janssen, and MSD Oncology; has received institutional research funding from Astellas Pharma, Medivation, AstraZeneca, Bayer, Genentech/Roche, Janssen, MSD Oncology, Pfizer, and Tokai Pharmaceuticals; and has received reimbursement for travel and accommodations expenses from Astellas Pharma, AstraZeneca Spain, Bayer Ipsen, Janssen, and Roche. Dr. Fizazi has received institutional honoraria from Astellas Pharma, Bayer, and Janssen; has served as a consultant or advisor to Amgen, Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Daiichi Sankyo Europe GmbH, Janssen, MacroGenics, MSD, Novartis, Orion, Pfizer, and Sanofi; and has received reimbursement for travel and accommodations expenses from AstraZeneca, Janssen, MSD, and Pfizer. Dr. Song reported no conflicts of interest.
REFERENCES
1. Olmos D, Lorente D, Alameda D, et al: Presence of somatic/germline homologous recombination repair mutations and outcomes in metastatic castration-resistant prostate cancer patients receiving first-line treatment stratified by BRCA status. 2023 ASCO Annual Meeting. Abstract 5003. Presented June 4, 2023.
2. Fizazi K, Azad A, Matsubara N, et al: TALAPRO-2: Phase 3 study of talazoparib + enzalutamide (ENZA) versus placebo + ENZA as first-line treatment for patients with metastatic castration-resistant prostate cancer harboring homologous recombination repair gene alterations. 2023 ASCO Annual Meeting. Abstract 5004. Presented June 4, 2023.
4. Song DY, George S, Zimberg S, et al: Real-world safety and effectiveness of radium-223 in patients with metastatic castration-resistant prostate cancer treated in the US: The non-interventional REASSURE study. 2023 ASCO Annual Meeting. Abstract 5050. Presented June 3, 2023.
