Daniel P. Petrylak, MD:
The first study we will discuss is the TALAPRO‑2 trial evaluating the combination of enzalutamide and talazoparib for mCRPC unselected for HRR status.⁵ These results were reported by Dr Neeraj Agarwal and colleagues at ASCO GU 2023.

TALAPRO-2 is a double‑blind phase III trial that randomized 805 patients with newly diagnosed mCRPC.⁵ HRR gene alterations including BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBM, MHR1, MRE11A and CDK12 were prospectively assessed. It is important to note that most of the patients enrolled on the study did not previously receive next-generation antiandrogens.

Patients were randomized to receive a combination of talazoparib 0.5 mg once daily (0.35 mg if moderate renal impairment) plus enzalutamide 160 mg once daily vs placebo plus enzalutamide. Stratification was by prior abiraterone or docetaxel for castration-sensitive prostate cancer (CSPC) and HRR mutation status.

The primary endpoint is rPFS by blinded independent central review (BICR) and a key secondary endpoint is OS. Other secondary endpoints include time to cytotoxic chemotherapy, PFS2 (by investigator), ORR, patient reported outcomes (PROs), and safety.

Daniel P. Petrylak, MD:
The arms were well balanced for age, median prostate-specific antigen (PSA), and sites of disease.⁵ Approximately 27% of patients in each arm had received abiraterone or docetaxel for CSPC, and 2 patients in each arm had received prior orteronel. Specifically, 5.2% to 6.2% of patients had received abiraterone and 21.4% to 23.1% had received docetaxel. This is a lower frequency than we have seen in other clinical trials. Approximately 20% of patients were HRR deficient.

Daniel P. Petrylak, MD:
The median rPFS by BICR was not reached in the talazoparib arm and was 21.9 months in the control arm (HR: 0.63; 95% CI: 0.51-0.78).⁵

Patients with HRR deficient disease had a median rPFS of 27.9 months with talazoparib vs 16.4 months with placebo (HR: 0.46; 95% CI: 0.30-0.70). In patients with HRR-nondeficient disease or unknown status, median rPFS was not reached with talazoparib and was 22.5 months in the control arm (HR: 0.70; 95% CI: 0.54-0.89). In patients with HRR-nondeficient disease by prospective tumor profiling, the median rPFS was not reached with talazoparib vs 22.1 months with placebo (HR: 0.66; 95% CI: 0.49-0.91).

There was a consistent rPFS benefit with talazoparib across all prespecified groups, including age, ECOG PS, Gleason score, stage at diagnosis, and sites of metastases.

The median OS was 36.4 months with talazoparib and was not reached in the placebo arm (HR: 0.89; 95% CI: 0.69-1.14).

Daniel P. Petrylak, MD:
The time to PSA progression, time to cytotoxic chemotherapy, and time to PFS2 were all improved with the addition of talazoparib.⁵

Objective response rates were better with the addition of talazoparib (61.7% vs 43.9%) as were CR rates (37.5% vs 18.2%) vs enzalutamide alone. There were similar levels of PR and SD.

Daniel P. Petrylak, MD:
Treatment‑emergent adverse events (TEAEs) affected 98.5% of the talazoparib arm vs 94.5% of the placebo arm, with 89.7% and 69.6% ruled treatment related, respectively.⁵ The rate of serious treatment related TEAEs was higher with talazoparib (19.6% vs 3.0%), but there were no treatment related grade 5 TEAEs compared with 2 (0.5%) in the placebo arm.

Among patients receiving talazoparib, 75% had a dose interruption, 56% had dose reductions, and 19% discontinued therapy vs 23%, 7%, and 12%, respectively among those receiving enzalutamide alone.

Daniel P. Petrylak, MD:
The most common all-cause TEAEs with talazoparib were anemia (65.8% any grade, 46.5% grade ≥3), neutropenia, fatigue, thrombocytopenia, leukopenia, back pain, and decreased appetite.⁵ The rate of TEAEs was consistent with individual agent profiles.

I think it is interesting that the talazoparib arm had 1 case of myelodysplastic syndromes (MDS) and 1 case of acute myeloid leukemia (AML). Pulmonary embolism also affected 10 patients (2.5%) in the talazoparib arm and 3 patients (0.7%) in the placebo arm, mostly grade 3. This is a theme we are seeing with other PARP inhibitors.

Daniel P. Petrylak, MD:
The phase III PROpel trial evaluated abiraterone plus olaparib vs abiraterone plus placebo as first‑line treatment of biomarker‑unselected mCRPC. In the primary analysis, abiraterone plus olaparib improved rPFS (24.8 vs 16.6 months; HR: 0.66; P <.001).⁶ The current presentation is the final prespecified OS analysis and was reported by Dr Noel Clarke and colleagues at ASCO GU 2023.⁷

PROpel enrolled 796 patients with mCRPC who had no previous therapy for mCRPC, although previous docetaxel for metastatic hormone sensitive prostate cancer (mHSPC) was allowed. No screening for HRR mutations was required.

The study randomized patients to receive olaparib 300 mg twice daily plus abiraterone 1000 mg once daily with prednisone or placebo plus abiraterone with prednisone. Stratification was by metastatic disease sites (bone only vs visceral vs other) and previous taxane for mHSPC. Treatment continued until radiographic progression or unacceptable toxicity and crossover was not permitted.

The primary endpoint was rPFS by investigator assessment with a sensitivity analysis by BICR. The key secondary endpoint was OS and other preplanned analyses were time to first subsequent therapy or death, PFS2, HRR status, safety, and tolerability.

Daniel P. Petrylak, MD:
The study arms were well balanced.^6,7 Approximately 28% of patients had HRR-mutated disease with HRR status unknown in only 2.3%. The prevalence of BRCA mutations was 11.8% in the olaparib arm vs 9.6% in the placebo arm. This rate of BRCA mutation is consistent with what we know about this patient population.

Daniel P. Petrylak, MD:
The median OS at the final prespecified analysis was 42.1 months with olaparib vs 34.7 months with placebo (HR: 0.81; 95% CI: 0.67-1.00; P = .0544). Currently, the data are 47.9% mature and the OS across subgroups was generally consistent with the intention-to-treat (ITT) population.⁷

Daniel P. Petrylak, MD:
The median OS in patients with HRR mutations was not reached with olaparib and 28.5 months with placebo (HR: 0.66; 95% CI: 0.45-0.95).⁷ No OS benefit was observed in patients with HRR-nonmutated disease (HR:0.89, 95% CI: 0.70-1.14).

Daniel P. Petrylak, MD:
The HR for the time to first subsequent therapy was 0.76. For PFS2, the HR was also 0.76.⁷

Daniel P. Petrylak, MD:
Two patients developed MDS/AML in the olaparib arm but the incidence of new primary malignancies and pneumonitis was balanced between the arms.⁷ Patient quality of life was similar across the study arms.

Daniel P. Petrylak, MD:
The toxicity profile was not surprising, with anemia the most common adverse event (AE) in the olaparib arm.⁷ The frequency of all-grade anemia was 49.7% with olaparib compared with 17.7% with placebo; grade ≥3 anemia affected 16.1% vs 3.3% of patients, respectively. The rate of pulmonary embolism was 7.3% with olaparib vs 2.3% with placebo and cardiac events occurred at 1.8% in both arms.

Daniel P. Petrylak, MD:
The phase III MAGNITUDE trial evaluated the addition of niraparib to first-line abiraterone acetate plus prednisone (AAP) vs placebo plus AAP. In the first interim analysis of MAGNITUDE, the addition of niraparib was associated was significant improvement in median rPFS in patients with HRR alterations vs the AAP alone arm.⁸ However, a futility analysis showed no benefit in patients without HRR alterations. This second interim analysis was reported by Dr Eleni Efstathiou and colleagues at ASCO GU 2023 and focuses on the HRR‑positive cohort after a median follow-up of 26.8 months.⁹

This study design is similar to PROpel and enrolled 670 patients with mCRPC who received no previous systemic therapy (AAP allowed if ≤4 months).⁹ The Brief Pain Inventory–Short Form worst pain score had to be ≤3. Patients were prescreened for HRR status before randomization using tissue and/or plasma assays for ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, and PALB2.

Randomization was to niraparib plus AAP or placebo plus AAP. Stratification was based on previous taxane-based chemotherapy for mCSPC, prior androgen receptor inhibitor for nonmetastatic CRPC or mCSPC, prior AAP for first-line mCRPC, and the presence of BRCA1/2 vs other HRR alterations.

The primary endpoint is rPFS by central review and secondary endpoints include OS, time to symptomatic progression, and time to cytotoxic chemotherapy.

Daniel P. Petrylak, MD:
BRCA1/2 alterations made up a little over 50% of the HRR alterations.⁹ The rate of visceral metastases was 24.1% in the niraparib arm vs 18.5% in the placebo arm, with the incidence of liver metastases 8.5% vs 6.2% and lung metastases 12.7% vs 8.5%. Median PSAs were similar, as was the rate of prior taxane‑based chemotherapy.

Daniel P. Petrylak, MD:
There was a large difference in rPFS and secondary outcomes in the BRCA subgroup.⁹ rPFS was 19.5 months with niraparib vs 10.9 months with placebo (HR: 0.55; 95% CI: 0.39-0.78). Median time to symptomatic progression was not reached vs 23.6 months with placebo (HR: 0.54; 95% CI: 0.35-0.85). Median time to the initiation of cytotoxic chemotherapy was not reached vs 27.3 months in the placebo arm (HR: 0.56; 95% CI: 0.35-0.90).

Daniel P. Petrylak, MD:
Safety was consistent with the previous analysis, and the most frequent AEs with niraparib were anemia (50.0%), hypertension (33.0%), and constipation (33.0%).⁹

Daniel P. Petrylak, MD:
The PARP inhibitor rucaparib has FDA accelerated approval for patients with deleterious BRCA mutation (germline and/or somatic)-associated mCRPC who have been treated with AR-directed therapy and a taxane-based chemotherapy.¹²

TRITON3 is the confirmatory phase III trial of rucaparib vs physician’s choice of docetaxel or second-generation androgen receptor pathway inhibitor (ARPi) in patients with mCRPC and a BRCA or ATM alteration.¹³ The current interim analysis, presented by Dr Alan Bryce and colleagues at ASCO GU 2023, reports primary endpoints of rPFS, preliminary OS data, and subgroup analyses.

TRITON3 enrolled 405 patients with BRCA1/2 or ATM mutations who progressed on a next-generation antiandrogen in any setting.^13,14 Patients could not have received prior PARP inhibitor or chemotherapy for CRPC. Randomization was 2:1 to rucaparib 600 mg twice daily in 28-day cycles or physician’s choice of docetaxel 75 mg/m² in 21-day cycles (max 10 cycles), abiraterone 1000 mg once daily, or enzalutamide 160 mg once daily, with prednisone coadministered with docetaxel and abiraterone. Stratification was by ECOG PS, the presence/absence of hepatic metastases, and genetic alteration. Treatment continued until radiographic progression or discontinuation for other reasons. Crossover from physician’s choice to rucaparib was optional following disease progression.

The primary endpoint is rPFS by independent radiology review (IRR) and key secondary endpoints are OS and ORR by IRR.

Daniel P. Petrylak, MD:
The study arms were well balanced. BRCA2 was the most common molecular alteration, at 58% to 68% across therapy groups. BRCA1 alterations occurred in approximately 11% of patients and ATM alterations in 20% to 32%.^13,14 Baseline PSAs, Gleason scores, and measurable disease were similar between arms.

Daniel P. Petrylak, MD:
The median rPFS in the BRCA‑altered subgroup at the time of this interim analysis was 11.2 months with rucaparib vs 6.4 months with physician’s choice (HR: 0.50; 95% CI: 0.36-0.69).^13,14

Daniel P. Petrylak, MD:
The median rPFS in the ITT population was 10.2 months with rucaparib and 6.4 months with physician’s choice (HR: 0.61; 95% CI: 0.47-0.80).^13,14

Daniel P. Petrylak, MD:
There was no rPFS benefit in the ATM-mutated subgroup, with a median rPFS of 8.1 months with rucaparib vs 6.8 months with physician’s choice (HR: 0.95; 95% CI: 0.59-1.52).^13,14

Daniel P. Petrylak, MD:
There was a rPFS benefit in the BRCA subgroup with rucaparib vs either docetaxel or second-generation ARPi therapy in the physician’s choice arm.^13,14 The rPFS with rucaparib was 11.2 months, 8.3 months with docetaxel, and 4.5 months with second-generation ARPi.

Daniel P. Petrylak, MD:
The median OS in the BRCA1/2 subgroup was 24.3 months with rucaparib vs 20.8 months with physician’s choice of therapy, but these data are immature.^13,14

Daniel P. Petrylak, MD:
Among patients receiving rucaparib, 60% had 1 or more grade ≥3 TEAE vs 61% with docetaxel and 44% with second-generation ARPi.^13,14 The most common TEAEs were anemia, asthenia/fatigue, nausea, and neuropathy. The incidence of nausea and anemia were much higher in the rucaparib arm, but neuropathy was more common with docetaxel. No cases of MDS or AML were reported. Blood transfusions were required in 29% of patients receiving rucaparib.

Daniel P. Petrylak, MD:
ARASENS was a randomized phase III trial of darolutamide plus ADT and docetaxel vs placebo plus ADT and docetaxel in patients with newly diagnosed mHSPC. In the primary analysis, the addition of darolutamide was associated with a significant reduction in the risk of death vs placebo.¹⁶

ARASENS enrolled 1305 patients with newly diagnosed mHSPC.^16,17 Patients were randomized to receive darolutamide 600 mg orally twice daily in combination with ADT and docetaxel 75 mg/m² on Day 1 of six 28-day cycles or placebo with ADT and docetaxel. The usual way to administer docetaxel is 21-day cycles. Stratification was based on the extent of disease and alkaline phosphatase level. Treatment continued until symptomatic disease progression, change in neoplastic treatment, unacceptable toxicity, withdrawal, or nonadherence.

The primary endpoint was OS. Secondary endpoints were tested hierarchically in the following order: time to CRPC, time to pain progression, symptomatic skeletal event (SSE)-free survival, time to first SSE, time to initiation of subsequent anticancer therapy, time to worsening of physical symptoms, time to first opioid use, and safety.

Daniel P. Petrylak, MD:
The initial analysis of ARASENS did not define high‑volume and high‑risk disease, so they retrospectively looked at the data using the criteria from the CHAARTED and LATITUDE trials.^17,18 The CHAARTED criteria for high volume disease are visceral metastases or ≥4 bone metastases with ≥1 beyond the vertebral column/pelvis.¹⁹ The LATITUDE criteria for high-risk require ≥2 of the following risk factors: Gleason score ≥8, ≥3 bone metastases, and/or visceral metastasis.²⁰

Daniel P. Petrylak, MD:
The darolutamide arm had 497 patients with high-volume disease vs 508 patients in the placebo arm.^17,18 Low-volume disease was less common, with 154 and 146 patients, respectively.

A similar number of patients had high-risk disease in both the darolutamide and placebo arms, 452 vs 460, respectively.

Daniel P. Petrylak, MD:
For high‑volume disease the median OS was 42.4 months with placebo and not reached for the darolutamide arm (HR: 0.69; 95% CI: 0.57-0.82).^17,18 For low‑volume disease, the median OS was not reached in either arm (HR: 0.68; 95% CI: 0.41-1.13) and the curves separated a little later than the high‑volume disease.

Daniel P. Petrylak, MD:
For patients with high‑risk disease, the median OS was 43.2 months with placebo and not reached with darolutamide (HR: 0.71; 95% CI: 0.58-0.86).^17,18 For low-risk disease, median OS was not reached in either arm (HR: 0.62; 95% CI: 0.42-0.90).

Daniel P. Petrylak, MD:
The time to progression to CRPC was significantly prolonged with the addition of darolutamide. The HR for high-volume disease is 0.41 (95% CI: 0.34-0.49) and for low-volume disease is 0.21 (95% CI: 0.14-0.33).^17,18 The median time to CRPC was not reached with darolutamide in either high- or low-volume disease.

Daniel P. Petrylak, MD:
The median time to CRPC was also not reached with darolutamide in either low- or high-risk disease.^17,18

Daniel P. Petrylak, MD:
Examining other endpoints such as pain progression, first symptomatic skeletal event, next therapy, and worsening symptoms by disease volume and risk found similar benefit irrespective of risk or volume.^17,18

Daniel P. Petrylak, MD:
TEAEs were also similar across disease volume and risk status.^17,18

Daniel P. Petrylak, MD:
Patients with localized prostate cancer may live for many years either with or without disease; therefore, toxicity plays an important role in treatment selection.²¹ For patients with localized prostate cancer, the assumption has been that stereotactic body radiotherapy (SBRT) and surgery have similar anticancer efficacy and safety, but they have not been formally compared.

The phase III PACE trial is comparing SBRT vs surgery for localized prostate cancer according to risk level.²² The current report compares SBRT and surgery in cohort A of the trial and was presented by Dr Nicholas John van As and colleagues at ASCO GU 2023. Cohort A of the PACE trial enrolled 123 patients with low or intermediate‑risk localized prostate cancer considered candidates for surgery. Other requirements included T1c-T2c disease, Gleason score ≤3+4, PSA ≤20 ng/mL, and no prior ADT. Patients were randomized to receive SBRT at 36.25 Gy in 5 fractions or surgery.

Coprimary endpoints were urinary incontinence (number of absorbent pads required per day) and Expanded Prostate Cancer Index (EPIC) bowel bother subdomain score, both measured using EPIC‑26. Secondary endpoints were patient‑reported outcomes (PROs), clinician‑assessed toxicity, biochemical/clinical failure, disease-free survival (DFS), and OS.

Daniel P. Petrylak, MD:
Overall, baseline characteristics were well balanced. Within the overall patient population, 92% had intermediate‑risk disease, 79% had a 3+4 Gleason score, and 65% of patients had PSA <10 ng/mL.²²

Daniel P. Petrylak, MD:
The coprimary endpoints were urinary incontinence and EPIC bowel bother score.²² There was a higher rate of urinary incontinence following surgery, with 15 out of 32 patients (46.8%) using any number of urinary pads compared with only 2 out of 44 patients (4.5%) who received SBRT. There was more bowel bother following SBRT, with a mean EPIC subdomain score of 88.7 vs 97.3 with surgery.

Daniel P. Petrylak, MD:
Interestingly, surgery was associated with significantly worse sexual subdomain scores at 2 years, at 29.3 vs 57.7 (P ≤.001).²² Urinary incontinence, urinary obstructive, and bowel subdomain scores were similar in both groups.

Daniel P. Petrylak, MD:
Examining safety outcomes by grade, 100% of patients experienced gastrointestinal toxicity within 2 years with no cases of grade ≥2 toxicity recorded in either group.²² GU toxicity was also very similar in both groups, with 90.7% of patients developing grade 0/1 toxicity and 9.3% developing grade ≥2 toxicity.