(UroToday.com) The 2024 European Association of Urology (EAU) annual congress held in Paris, France between April 5th and 8th was host to an abstract session on treatment intensification to improve prostate cancer outcomes. Dr. Junlong Zhuang presented the efficacy and safety outcomes of a single arm trial evaluating neoadjuvant pamiparib plus abiraterone acetate and androgen deprivation therapy (ADT) for high-risk/very high-risk localized prostate cancer.
Preclinical models have suggested synergistic mechanisms of action for Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and androgen receptor signaling inhibitors (ARSIs). PARPi upregulates androgen receptor signaling, enhancing ARSI activity. Conversely, ARSIs inhibit the transcription of some HRR genes, inducing an HRR deficiency-like state, thus potentiating PARPi activity.1-3These mechanisms of action suggest that the PARPi/ARSI combination may have clinical efficacy, irrespective of homologous recombination repair mutational status. This combination has not yet been evaluated in the neoadjuvant setting. In this study, the investigators evaluated the efficacy and safety of neoadjuvant pamiparib, abiraterone acetate, and ADT in high- and very high-risk localized prostate cancer prior to radical prostatectomy.
In this phase II single-arm neoadjuvant trial, patients with clinically localized, high- or very-high risk prostate cancer (defined as Gleason Score ≥ 8 and/or cT3-4N0-1 and/or PSA≥ 20 ng/mL) were enrolled. Patients received pamiparib plus abiraterone acetate and ADT for four months followed by a radical prostatectomy. The primary study objective was the rate of pathological complete response (pCR) or minimal residual disease (MRD). MRD was defined as ≤0.5cm of tumor or residual cancer burden ≤0.25 cm3 (RCB = tumor volume x cellularity). Secondary endpoints included:
- PSA response
- Pathologic stage
- 12-months PSA recurrence rates
- Safety outcomes
A total of 30 patients were enrolled, of whom 29 (HRRm n=7) completed the full course of study treatment and underwent subsequent radical prostatectomy. One patient declined surgery for personal reasons and received further systemic therapy. The median patient age was 66 years (range: 41 – 77 years). The clinical characteristics were typical of patients with high- and very-high-risk disease: the median PSA was 34.4 ng/ml (range: 10.8 – 204 ng/ml), the clinical stage was cT3 in 27/30 patients, Gleason Score was 8 – 10 in 20/30 patients, and 9/30 had clinical node-positive disease.
Following four months of therapy, the median pre-RP PSA was 0.103 ng/ml (range 0.006 – 1.1 ng/ml). The final pathologic results showed that eight pts (27.5%) achieved pCR or MRD (pCR: 3, MRD: 5). 18/30 patients were pathologically downstaged, and none experienced disease progression. Compared to patients with an HRR wild type (HRRwt), those with HRR mutations had no difference in pCR or MRD. A positive surgical margin was observed in 2/29 patients, all of whom were T3 stage patients. No grade 3/4 drug-related adverse event was observed. The most common grade 1-2 adverse events were anaemia (48.2%), AST/ALT increases (34.4%), and hypertriglyceridemia (44.8%).
Thus, the investigators concluded that neoadjuvant therapy with 4 months of pamiparib plus abiraterone acetate and ADT was effective and safe in patients with clinically localized, high- and very high-risk prostate cancer.
Presented by: Junlong Zhuang, Affiliated Drum Tower Hospital, Department of Urology, Nanjing, China
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 European Association of Urology (EAU) annual congress, Paris, France, April 5th – April 8th, 2024
References:
- Asim M, Tarish F, Zecchini HI, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun 2017; 8: 374.
- Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov 2012; 2: 1134-49.
- Li L, Karanika S, Yang G, et al. Androgen receptor inhibitor-induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer. Sci Signal 2017; 10: eaam7479.