ASCO GU 2024: mCRPC in focus

mCRPC in focus at ASCO GU 2024

BRCAAway: Abiraterone, olaparib or both in mCRPC with HRR mutations

Maha Hussain (Robert H Lurie Comprehensive Cancer Center, Chicago, Illinois, USA) presented on the BRCAAway trial, which evaluates the efficacy of an androgen receptor inhibitor (ARi) versus a poly adenosine diphosphate-ribose polymerase inhibitor (PARPi) versus the combination of the two in people with mCRPC and mutations in the BRCA1/2 or ATM genes.

Deleterious germline or somatic HRR mutations are evident in ~20% of people with mCRPC

Promising synergism between PARPi and ARi has been shown preclinically.

BRCAAway procedure and endpoints

Eligible patients (mCRPC with no prior exposure to PARPi, ARi, or chemotherapy) received tumour next generation sequencing and germline testing. Patients shown to have inactivating BRCA1/2 and/or ATM alterations were randomised and received abiraterone + prednisone, olaparib monotherapy, or olaparib + abiraterone/prednisone.

• Primary endpoints: Radiographic progression free survival (rPFS), clinical assessment or death
• Secondary endpoints: Measurable disease response rate, prostate-specific antigen (PSA) response rate and adverse events

BRCAAway efficacy and safety findings

Hussain observed that the trial participants given abiraterone/prednisone + olaparib showed a longer median rPFS (39 months) than those given abiraterone + prednisone (8.4 months) or olaparib monotherapy (14 months). The rates of grade 3 events were 21%, 14% and 19%, respectively.

Neal Shore (Carolina Urologic Research Center, Myrtle Beach, USA) analyses the BRCAAway trial.

CONTACT-02: Cabozantinib + atezolizumab vs second novel hormonal therapy for mCRPC

Neeraj Agarwal (Huntsman Cancer Institute, University of Utah, Salt Lake City, USA) presented the findings of the phase 3 CONTACT-02 study.

People with mCRPC who have progressed on NHT have a poor prognosis (median overall survival <2 years), especially those with visceral or extra-pelvic nodal metastasis

Following novel hormonal therapy (NHT) failure, a second NHT or chemotherapy are the only available non-targeted treatments for these patients; chemotherapy use is limited by frailty, toxicity or patient preference.

What is cabozantinib?

Cabozantinib is a multitargeted tyrosine kinase inhibitor that can improve rPFS and overall survival (OS) in refractory mCRPC and a subgroup of men with visceral metastases⁵.

The COSMIC-021 trial showed that cabozantinib + atezolizumab is efficacious and tolerable in post-NHT mCRPC.

CONTACT-02 evaluated cabozantinib + atezolizumab versus a second NHT in people with mCRPC and extra-pelvic soft tissue metastasis after progression on a first NHT. Eligible patients were randomised and received cabozantinib + atezolizumab, or a second NHT (abiraterone + prednisone, or enzalutamide).

Dual primary endpoints

rPFS and OS in all randomised patients.

CONTACT-02 summary findings

• Cabozantinib + atezolizumab significantly improved rPFS compared with a second NHT in mCRPC patients with extrapelvic nodal or visceral disease
• Median rPFS was significantly longer for patients receiving cabozantinib + atezolizumab than those receiving a second NHT (6.3 vs 4.2 months; HR 0.65, 95% CI, 0.50–0.84; P=0.0007), including those with liver metastasis (6.0 vs 2.1 months; HR 0.47, 95% CI, 0.30–0.74) or prior docetaxel treatment for metastatic castration-sensitive prostate cancer (8.8 vs 4.1 months; HR 0.55, 95% CI, 0.32–0.96)
• OS analysis is incomplete
• Rates of grade 3–4 treatment-related adverse events were 33% with cabozantinib + atezolizumab versus 8% with a second NHT

The ACE study: Cognitive function with abiraterone acetate + prednisolone vs enzalutamide

Amit Bahl (University Hospitals Bristol, UK) presented the ACE study, a multicentre prospective evaluation of cognitive function in patients with mCRPC treated with abiraterone acetate + prednisolone or enzalutamide. Abiraterone acetate + prednisolone, and enzalutamide, are approved for mCRPC.

There is a limited understanding of the impact of abiraterone acetate + prednisolone or enzalutamide on cognition, fatigue and depression. The ACE study aims to help close this gap.

Assessment of cognitive function in ACE

The cognition of eligible patients (≥18 years, mCRPC diagnosis, able to provide informed consent) was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) assessment tool prior to initiating study treatments. CANTAB assessment was repeated at 3, 4 and 6 months. Cognitive function and fatigue were measured with the Functional Assessment of Cancer Therapy tool and depression with the Patient Health Questionnaire 9.

ACE key findings

Bahl concluded that overall cognitive outcomes were comparable in patients receiving either treatment at 3 and 6 months, as were outcomes for the spatial working memory, rapid information processing and spatial information processing domains. However, participants taking enzalutamide had significantly poorer results than those taking abiraterone acetate + prednisolone for the reaction time task at both timepoints.

Patients taking enzalutamide also had more fatigue and depression than those taking abiraterone acetate + prednisolone at both assessment points.

“I think these are really important studies as they continue to help us in our conversations that we have with patients.” Neal Shore assesses the ACE trial.

Learn more about how unmet needs in mCRPC are being addressed

Combination therapies: Use in mCRPC and high-risk localised disease

Why combine PARPi and ARPi for prostate cancer?

Ravindran Kanesvaran (National Cancer Centre Singapore) explained the rationale for combining poly adenosine diphosphate-ribose polymerase inhibition (PARPi) and androgen receptor pathway inhibition (ARPi) in patients with homologous recombination repair (HRR) deficient or non-deficient tumours.

• ARPi upregulates PARP activity and downregulates HRR gene expression, inducing a phenotype similar to HRR deficiency
• PARPi disrupts single strand break repair, leading to double strand breaks
• PARPi supresses AR transcriptional activity and may attenuate resistance to ARPi

Preclinical data suggest that co-inhibition of AR and PARP can benefit tumours with or without mutations, noted Kanesvaran.

ARPi and PARPi metanalysis of mCRPC clinical trials

Supporting this, in a metanalysis of PROpel, TALAPRO-2 and MAGNITUDE, PARPi combined with ARPi increased overall survival and progression free survival (PFS)⁶ relative to placebo plus ARPi in mixed cohorts with metastatic castration resistant prostate cancer (mCRPC).

When stratified by HRR status, there was a significant PFS benefit with the combination versus placebo plus ARPi for all subgroups, but with the largest effect seen in participants whose tumours were HRR deficient or BRCA mutated, rather than HRR non-deficient⁶.

ARPi and PARPi enter clinical practice for mCRPC

Kanesvaran noted that the FDA and EMA have approved ARPi + PARPi for specific subpopulations. Olaparib + abiraterone (PROpel) and niraparib + abiraterone acetate + prednisone (MAGNITUDE) are approved for men with BRCA-mutated mCRPC, and talazoparib + enzalutamide (TALAPRO-2) has been approved by the FDA for those with HRR-mutated mCRPC (decision pending from EMA as of January 2024).

Darolutamide + androgen deprivation therapy for high-risk/very-high risk localised prostate cancer

Junlong Zhuang (Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, China) presented data from a phase 2 trial on darolutamide + androgen deprivation therapy (ADT) for localised, high/very-high risk prostate cancer.

Who were the eligible patients?

Eligible patients had high-risk/very high-risk localised prostate cancer, with an Eastern Cooperative Oncology Group performance status ≤1 and at least one of:

• Primary tumour stage ≥T3
• Serum prostate-specific antigen (PSA) ≥20 ng/mL
• Gleason score ≥8
• Regional lymph node involvement

Enrolled participants received 6 months of darolutamide + ADT prior to radical prostatectomy.

• Primary endpoint: pathological response rate; the proportion of patients with pathologic complete response (pCR) or minimal residual disease (MRD)
• Secondary endpoints included PSA progression-free survival, positive surgical margins rate, downstaging rate

What were the results?

Thirty patients received radical prostatectomy. The median age of patients was 71.0 years. Baseline median PSA level was 37.8 ng/mL. Most patients had very high risk, localised prostate cancer (93.3%).

Of the 30 men involved in the trial, 27 (90%) achieved undetectable PSA levels (<0.01 ng/mL). The pCR rate was 6.7% and the MRD rate was 33.3%, resulting in a pathological response rate of 40.0%.

Twenty patients (66.7%) achieved downstaging; four patients (13.3%) had positive surgical margins.

The researchers therefore concluded that darolutamide + ADT for 6 months prior to radical prostatectomy is effective for patients with localised, high/very-high risk prostate cancer.

Neal Shore (Carolina Urologic Research Center, Myrtle Beach, USA) provides an overview of real-world research data presented at ASCO GU.