ASCO GU 2023: Rucaparib for Metastatic Castration-Resistant Prostate Cancer (mCRPC): TRITON3 Interim Overall Survival and Efficacy of Rucaparib vs Docetaxel or Second-Generation Androgen Pathway Inhibitor Therapy

(UroToday.com) The PARP inhibitor (PARPi) rucaparib previously received accelerated FDA approval for the treatment of metastatic castration resistant prostate cancer (CRPC) associated with a deleterious alteration in either the BRCA1 or BRCA2 genes, known mediators of homologous recombination, based on data from the open-label phase II TRITON2 study. As previously reported, qualifying patients in TRITON2 with mCRPC and a BRCA1/2 alteration experienced an objective response rate (ORR) of 43.5% and a PSA response rate of 54.8%. TRITON3, as presented here at the 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, was the obligatory confirmatory study mandated by prior accelerated approval.

Dr. Alan Haruo Bryce presents on behalf of the study team interim overall survival data of TRITON3, A Phase 3 Study of Rucaparib vs Physician’s Choice of Therapy in Metastatic Castration-Resistant Prostate Cancer Associated with Homologous Recombination Deficiency (NCT029775934). Eligibility criteria included having received at least one prior androgen receptor pathway inhibitor (ARPI) in any setting, chemotherapy-naïve in the CRPC setting, and harboring a deleterious germline or somatic alteration in BRCA1, BRCA2, or ATM, as confirmed on central or local testing. Randomization was 2:1 between rucaparib (600 mg BID) and physician’s choice of either docetaxel or second ARPI (abiraterone acetate or enzalutamide, whichever the patient had not yet received).

Dr. Bryce highlights that the comparator arm was purposefully designed to allow docetaxel, a standard and highly active therapy, as opposed to a second ARPI, and making this the first study to compare PARPi to docetaxel. Patients who progressed on physician’s choice had the option to receive rucaparib. The primary endpoint was radiographic progression-free survival (rPFS) by independent review in both BRCA1/2 group and also the entire population (IIT). Secondary endpoints included overall survival (OS) and ORR via independent review.

As of August 25, 2022, 302 patients with BRCA1/2 and 103 with ATM alterations were randomized. Baseline characteristics were well-balanced between groups overall. Overall survival maturity was 53.6% in the BRCA1/2 group and 59% in the IIT group. The data presented included the physician’s choice group collectively, as well as by therapy received (i.e., docetaxel or abiraterone acetate/enzalutamide). In the BRCA1/2 population, median rPFS was 11.2 months (95% CI 9.2-13.8) in those patients treated with rucaparib (n=201), which was greater than the physician’s choice group collectively (n=101, 6.4 months [5.4-8.3], p<0.0001), docetaxel (n=60, 8.3 months [6.1-9.9], p=0.0009), and abiraterone/enzalutamide (n=41, 4.5 months [3.3-5.8], p<0.0001).

Hazard ratios (HR) with 95% CIs were as follows for rucaparib versus physician’s choice (0.50, [0.36-0.69]), docetaxel (0.53 [CI 0.37-0.77]), and abiraterone/enzalutamide (0.38 [0.25-0.58]).

The ITT group showed similar, but more modest trends toward improved outcomes with rucaparib. Analysis of the ATM group, separate from the entire IIT population, revealed no significant difference in outcome with rucaparib treatment.

Overall survival data demonstrated no statistically significant difference in overall survival, although the authors highlight a trend toward improved OS with rucaparib. Given this variance in effect based on mutated gene status, the authors also shared the distribution within each gene with respect to germline or somatic.

No new safety signals were observed. The most common treatment emergent adverse events (TEAEs) in the rucaparib, docetaxel, and abiraterone/enzalutamide groups was asthenia/fatigue (61.1%, 67.6% and 57.6%, respectively) and the most common grade ≥3 TEAEs were anemia (23.7%), neutropenia (14.1%), and hypertension (10.2%), also respectively. No cases of MDS and/or AML were observed.

In conclusion, Dr. Bryce reports that TRITON3 met its primary endpoint of prolonged rPFS in both the BRCA1/2 and IIT groups. No rPFS benefit was observed in patients with ATM, suggesting that the clinical relevance of an ATM mutation for HR repair remains in question. The use of docetaxel as a comparator in the physician’s choice arm, as well as sharing the therapy-based breakdown of responses, strengthens the value of these data and the impact on clinical care for patients with relevant BRCA1/2 alterations. Of significant note, when incorporating these data into practice, as 75% of eligible patients in the Physician’s Choice are received rucaparib following progression (84 patients eligible to cross, 63 agreed). An absence of OS improvement thus far should be noted, although a chemotherapy-free option for these patients will have positive patient impact.

Presented by: Alan Haruo Bryce, MD, Mayo Clinic, Phoenix, Arizona

Written by: Jones Nauseef, MD, PhD, Assistant Professor of Medicine within the Division of Hematology and Medical Oncology, Sandra and Edward Meyer Cancer Center, and Englander Institute for Precision Medicine Weill Cornell Medicine and Assistant Attending physician at NewYork-Presbyterian Hospital. @DrJonesNauseef on Twitter during the 2023 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, Thurs, Feb 16 – Sat, Feb 18, 2023.

Related Content:

PARP Inhibitors in Metastatic Castration Resistant Prostate Cancer - Elena Castro

Interim Overall Survival Analysis of TRITON3: Rucaparib vs Physician's Choice of Therapy in mCRPC with Homologous Recombination Deficiency - Alan Bryce

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