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Responding to unmet needs for metastatic castration-resistant prostate cancer
mCRPC in focus

Congress highlights

Last updated:1st Oct 2024
Published:7th Jun 2024

ESMO 2024 mCRPC update

Read key developments for metastatic castration-resistant prostate cancer (mCRPC) from the European Society for Medical Oncology (ESMO) Congress 2024, covering phase 2 and 3 clinical trial developments and investigational treatments.

Phase 3 clinical trial round-up for mCRPC at ESMO 2024

CONTACT-02

What effect did cabozantinib combined with atezolizumab have on patients with mCRPC? Silke Gillessen (Oncology Institute of Southern Switzerland, Bellinzona) reviews the CONTACT-02 clinical trial. View transcript.

Patients with mCRPC whose disease has advanced on novel hormonal therapy (NHT) have poor prognosis and limited treatment options.1 The phase 3 CONTACT-02 trial, which enrolled men with mCRPC who had previously been treated with one NHT,2 demonstrated a median progression-free survival (PFS) of 6.3 months with cabozantinib plus atezolizumab, versus 4.2 months with a second NHT, giving a significant HR of 0.65, favoring cabozantinib plus atezolizumab (95% CI, 0.50–0.84; P=0.0007).1

Neeraj Agarwal (Huntsman Cancer Institute, Salt Lake City, Utah, USA) presented final overall survival (OS) data from CONTACT-02 at ESMO 2024.1 The final median OS for cabozantinib plus atezolizumab was 14.8 months, versus 15.0 months for a second NHT, and did not achieve statistical significance (HR, 0.89; 95% CI, 0.72–1.10; P=0.030). However, pre-specified subgroup analysis indicated OS benefits from cabozantinib plus atezolizumab versus a second NHT in participants with liver or bone metastasis. Grade 3–4 treatment-emergent adverse events (TEAEs) occurred in 40% for cabozantinib plus atezolizumab, and 8% for the second NHT group. There were no grade 5 TEAEs.

[Cabozantinib plus atezolizumab], a treatment option with a novel mechanism of action, may be useful for selected patients with mCRPC who have progressed on an NHT
Neeraj Agarwal

SPLASH

SPLASH is an open-label phase 3 trial evaluating the efficacy and safety of an investigative prostate-specific membrane antigen (PSMA)-targeted small molecule radioligand, 177Lu-PNT2002, in mCRPC after androgen receptor pathway inhibitor (ARPI) therapy. The study is enrolling PSMA positron emission tomography (PSMA-PET)-positive patients with mCRPC who progressed on a previous ARPI (without chemotherapy) for CRPC. The primary outcome is radiographic PFS (rPFS), assessed by blinded independent central review using RECIST 1.1/PCWG3, or death from any cause.3

Median rPFS was significantly improved for patients receiving 177Lu-PNT2002 compared with an alternative ARPI (enzalutamide or abiraterone), at 9.5 months versus 6.0 months, with an HR of 0.71 (95% CI, 0.55–0.92; P=0.0088)

The incidence of TEAEs leading to treatment discontinuation and grade ≥3 TEAEs were lower for 177Lu-PNT2002 than ARPI or androgen receptor signaling inhibitor (1.9% [5/269] versus 6.2% [8/130], and 30.1% versus 36.9%, respectively). The most common TEAEs with 177Lu-PNT2002 were fatigue (53.5%), dry mouth (37.2%), and nausea (31.2%).

These initial data underscore the importance of PSMA-targeted radioligand therapies, including 177Lu-PNT2002, as potential treatment options for patients who have limited choices after progressing on ARPI therapy.
Oliver Sartor (Mayo Clinic, Rochester, Minnesota, USA)

PEACE-3

Silke Gillessen reviews PEACE-3, a phase 3 clinical trial investigating enzalutamide and radium-223 in patients with mCRPC and bone metastases. View transcript.

Silke Gillessen (Oncology Institute of Southern Switzerland, Bellinzona) presented data from the PEACE-3 phase 3 trial, which is investigating first-line enzalutamide and radium-223 versus enzalutamide alone in patients with mCRPC and bone metastasis.4

The HR for rPFS was 0.69 (95% CI, 0.54–0.87; P=0.0009), with a median rPFS of 16.4 months for enzalutamide and 19.4 months for the combination. In the preplanned interim analysis, performed at 80% of OS events, median OS was 35 months for enzalutamide, and 42.3 months for the combination (HR, 0.69; 95% CI, 0.52–0.90; P=0.0031). The most frequent grade ≥3 TEAEs in the combination arm were hypertension (34%), fatigue (6%), fracture (5%), anemia (5%), and neutropenia (5%).

PEACE-3 showed that adding radium-223 to enzalutamide as first-line therapy for mCRPC significantly improved rPFS, compared with enzalutamide alone. A final OS analysis is planned to confirm these results.

Sequencing radium-223 and docetaxel for bone-dominant mCRPC

“I really think this is the future.” Silke Gillessen rounds up the latest data on radioligand treatments for mCRPC. View transcript.

The phase 2 RAPSON data, presented at ESMO 2024 by study author Vincenza Conteduca (University of Foggia, Italy) provided clinical evidence toward using radium-223 for symptomatic bone-dominant mCRPC.5

For patients progressing on APRI, is docetaxel or radium-223 the preferred choice?
Vincenza Conteduca

The 70 study participants were randomly assigned to treatment with either radium-223 (six monthly injections) or docetaxel (10 cycles every 3 weeks), after which they could cross over to the alternative treatment if needed.

The primary endpoint was the change in health-related quality of life (HRQoL), assessed with the Functional Assessment of Cancer Therapy Prostate (FACT-P) questionnaire (baseline to week 12). The mean change favored the group initiated on radium-223, with a difference of 3.87 points (95% CI, −9.14 to 18.89). Although both groups had a deterioration in HRQoL from baseline, the change was statistically significant only in the docetaxel group.

A responder analysis at week 12 showed a higher incidence of responders for pain intensity and interference with daily activities due to pain for radium-223 compared with docetaxel. Radium-223 was also better tolerated then docetaxel, with two versus seven discontinuations and one versus nine dose reductions. PFS was not significantly different between the two treatments.

The ongoing RAPSON trial supports radium-223 prior to chemotherapy in bone-dominant symptomatic mCRPC, with clinical benefits for both HRQoL and tolerability.

An investigational treatment that could overcome resistance to ARPI

Do immune checkpoint inhibitors have a place in the treatment of mCRPC? Silke Gillessen gives her view. View transcript.

mCRPC that advances on ARPI could be driven by AR signaling.6,7 BMS-986365 is an orally administered ligand-directed degrader targeting the AR through AR antagonism and degradation. This dual mechanism could enable BMS-986365 to achieve stronger inhibition of AR signaling compared with conventional antagonists.8

Dana Rathkopf (Memorial Sloan Kettering Cancer Center, New York, USA) presented results from a first-in-human phase 1 trial of BMS-986365 in progressive mCRPC.9 The data were from the part B dose expansion phase, using 400, 600, and 900 mg twice daily (n=20 each).

Enrolled patients had progressed on at least one ARPI and had undergone taxane chemotherapy. Prior therapy included chemotherapy (n=31; 46%), enzalutamide (n=51; 75%), abiraterone (n=44; 65%), and both enzalutamide and abiraterone (n=31; 46%).

During a median 14.8 months of follow-up, the most common TEAEs were asymptomatic prolonged corrected QT interval (47%, including 9% at grade 3), bradycardia (34%), and fatigue (21%). Grade 3 QTc prolongation was managed by dose reduction. There were no grade 4 or 5 TEAEs, and no TEAEs leading to treatment discontinuation.

At the point of data cutoff, 48% of the participants had achieved PSA30, and 32% achieved PSA50. Median rPFS was 6.3 months. PSA30 and rPFS increased with dose:

  • PSA30: 30% (400 mg), 45% (600 mg), 70% (900 mg)
  • rPFS: 5.5 months (400 mg), 5.5 months (600 mg), 8.3 months (900 mg)

42% of patients were alive and free of radiographic progression at 6 months

PSA responses were observed both in patients with wild-type AR ligand binding domain and in those with mutations.

In patients with mCRPC heavily pretreated post-ARPI, BMS-986365 was tolerated and showed a manageable safety profile. BMS-986365 could overcome resistance to current ARPI in patients with progressive mCRPC, regardless of AR status. A phase 3 trial is being planned.

“The androgen-receptor degraders are very promising because the androgen receptor is still a very important pathway.” Silke Gillessen considers the future of mCRPC treatment. View transcript.

References

  1. CONTACT-02: Phase 3 study of cabozantinib (C) plus atezolizumab (A) vs second novel hormonal therapy (NHT) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). 2024. https://meetings.asco.org/abstracts-presentations/229876
  2. NCT04446117, 2024. Study of cabozantinib in combination with atezolizumab versus second NHT in subjects with mCRPC (CONTACT-02). https://clinicaltrials.gov/study/NCT04446117
  3. NCT04647526, 2024. Study evaluating mCRPC treatment using PSMA [Lu-177]-PNT2002 therapy after second-line hormonal treatment (SPLASH). https://clinicaltrials.gov/study/NCT04647526
  4. NCT02194842, 2024. Phase III radium-223 mCRPC-PEACE III. https://clinicaltrials.gov/study/NCT02194842
  5. NCT03230734, 2024. Sequencing of radium-223 and docetaxel in symptomatic bone-only metastatic castration-resistant prostate cancer (RAPSON). https://clinicaltrials.gov/study/NCT03230734
  6. Fizazi, 2019. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. https://www.doi.org/10.1016/s1470-2045(19)30082-8
  7. Davis, 2019. Enzalutamide with standard first-line therapy in metastatic prostate cancer. https://www.doi.org/10.1056/nejmoa1903835
  8. Xu, 2024. Abstract ND02: Discovery of BMS-986365, a ligand-directed androgen receptor degrader (AR LDD) with a dual mechanism-of-action and best-in-class potential, for the treatment of advanced prostate cancer. https://www.doi.org/10.1158/1538-7445.am2024-nd02
  9. NCT04428788, 2024. Study to evaluate the safety and tolerability of CC-94676 in participants with metastatic castration-resistant prostate cancer. https://clinicaltrials.gov/study/NCT04428788
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