Combination PARP with androgen blocker, regardless of HRR gene alterations showed benefit vs. androgen blocker alone.
Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC).
TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing.
Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9–30·2) for the talazoparib group and 24·6 months (14·4–30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months–not reached) for talazoparib plus enzalutamide and 21·9 months (16·6–25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51–0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3–4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group.
Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations.
Pfizer.
Less radiation is non-inferior, this is for low and intermediate-risk localized prostate cancer patients. Would like input from our radiation oncologists as to whether or not this adoptable?
Protons vs IMRT for localized prostate cancer showed no difference in outcome or quality of life. There will be longer f/u and other endpoints studied but the take-home message is that protons are not significantly better than photons.
Will we be replaced by AI? It seems that for radiologists, an AI system was better than the human counterpart in this study looking at prostate cancer diagnostic imaging. I doubt many of us would accept a solely computer-generated report, but this study highlights how AI may help as a supportive tool in the primary diagnostic setting. Of course, prospective validation will be needed.
10-year metastasis-free survival was 71.9% in the short-course ADT group (6 months) and 78% in the long-course ADT group (24 months). So, it seems the longer the duration, the better the outcome. 93% had a Gleason score of 7 or higher.
We know that combination PARP and antiandrogen is better than antiandrogen alone. I have wondered if we need antiancrogen on those patients. This shows that, YES, we do. The combination also was better than PARP inhibitor monotherapy in those patients carrying HRRm.
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