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ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician’s choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician’s choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or ‘all’ patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician’s choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR (single-nucleotide variant/genomic structural rearrangement)-negative and TP53 wild-type patients and TMPRSS2–ERG fusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53 -altered patients. In summary, ARPIs outperform taxanes and physician’s choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835 . In a biomarker-driven, outcome-adaptive platform trial for patients with metastatic castration-resistant prostate cancer, androgen receptor pathway inhibitors showed longer survival with respect to taxanes and physician’s choice treatment.

Up to 30% of patients with metastatic castration-resistant prostate cancer have deleterious mutations in genes involved in homologous recombination repair of DNA damage. The use of the PARP inhibitor olaparib in such patients was associated with longer progression-free survival and a longer time to pain progression than control therapy.

The PROfound trial showed that olaparib prolonged imaging-based progression-free survival among patients whose tumors contained defects in the homologous recombination repair genes BRCA1 , BRCA2 , or ATM . With longer follow-up, the trial now shows that olaparib prolonged overall survival in these patients. Toxic effects included anemia, nausea, and asthenia.

In a randomized trial involving men with metastatic prostate cancer with a DNA-repair defect, rucaparib was associated with longer progression-free survival than a control medication (11.2 vs. 6.4 months).

Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer. In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing. 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7–35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0–69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1–54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1–42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2–32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2–52·5) of 46 and 13 (30·2%; 17·2–46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9–72·5) of 28 and 13 (48·1%; 28·7–68·1) of 27. The most common grade 3–4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort. Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice. Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.

Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations. In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]), an Eastern Cooperative Oncology Group performance status of 0–2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing. Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1–22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2–39·6). The most common grade 3–4 treatment-emergent adverse events were anaemia (39 [31%] of 127 patients), thrombocytopenia (11 [9%]), and neutropenia (ten [8%]). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths. Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit–risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations. Pfizer/Medivation.

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.

Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase. This association provides a rationale for their co-inhibition for the treatment of metastatic castration-resistant prostate cancer (mCRPC), an area of unmet medical need. The phase 3 TALAPRO-2 study investigated combining the poly(ADP-ribose) polymerase inhibitor talazoparib with enzalutamide versus enzalutamide alone as first-line treatment of mCRPC. Patients were prospectively assessed for tumor alterations in DNA damage response genes involved in homologous recombination repair (HRR). Two cohorts were enrolled sequentially: an all-comers cohort that was enrolled first (cohort 1; N  = 805 (169 were HRR-deficient)), followed by an HRR-deficient-only cohort (cohort 2; N  = 230). We present results from the alpha-controlled primary analysis for the combined HRR-deficient population ( N  = 399). Patients were randomized in a 1:1 ratio to talazoparib or placebo, plus enzalutamide. The primary endpoint, radiographic progression-free survival, was met (median not reached at the time of the analysis for the talazoparib group versus 13.8 months for the placebo group; hazard ratio, 0.45; 95% confidence interval, 0.33 to 0.61; P  < 0.0001). Data for overall survival, a key secondary endpoint, are immature but favor talazoparib (hazard ratio, 0.69; 95% confidence interval, 0.46 to 1.03; P  = 0.07). Common adverse events in the talazoparib group were anemia, fatigue and neutropenia. Combining talazoparib with enzalutamide significantly improved radiographic progression-free survival in patients with mCRPC harboring HRR gene alterations, supporting talazoparib plus enzalutamide as a potential first-line treatment for these patients. ClinicalTrials.gov Identifier: NCT03395197 . In the homologous recombination repair-deficient population of TALAPRO-2, a placebo-controlled phase 3 trial, treatment of patients with metastatic castration-resistant prostate cancer with the poly(ADP-ribose) polymerase inhibitor talazoparib plus enzalutamide led to prolonged progression-free survival compared with placebo plus enzalutamide.

Circulating tumor DNA (ctDNA) in plasma cell free DNA (cfDNA) of cancer patients is associated with poor prognosis, but is challenging to detect from low plasma volumes. In metastatic castration-resistant prostate cancer (mCRPC), ctDNA assays are needed to prognosticate outcomes of patients treated with androgen receptor (AR) inhibitors. We develop a custom targeted cfDNA sequencing assay, named AR -ctDETECT, to detect ctDNA in limiting plasma cfDNA available from mCRPC patients in the Alliance A031201 randomized phase 3 trial of enzalutamide with or without abiraterone. Of 776 patients, 59% are ctDNA-positive, with 26% having high ctDNA aneuploidy and 33% having low ctDNA aneuploidy but displaying AR gain or structural rearrangement, MYC / MYCN gain, or a pathogenic mutation. ctDNA-positive patients have significantly worse median overall survival than ctDNA-negative patients (29.0 months vs. 47.4 months, respectively). Here, we show that mCRPC patients identified as ctDNA-positive using the AR -ctDETECT assay have poor survival despite treatment with potent AR inhibitors in a phase 3 trial. Liquid biopsy assays are important to prognosticate outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients treated with androgen receptor (AR) inhibitors. Here this group reports detecting circulating tumor DNA in limiting plasma cell-free DNA of mCRPC patients as prognostic marker of poor survival after AR treatment.

Metastatic castration-resistant prostate cancer remains incurable and is particularly aggressive in patients with alterations in DNA damage repair genes involved directly or indirectly in homologous recombination repair (HRR). In the primary analysis of TALAPRO-2, talazoparib plus enzalutamide significantly improved radiographic progression-free survival (rPFS) versus enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer harbouring HRR gene alterations. At primary analysis, overall survival was immature. Here we report final prespecified overall survival analysis, updated rPFS, safety, and patient-reported outcomes in the HRR-deficient cohort of TALAPRO-2. TALAPRO-2 is an ongoing international, randomised, double-blind, placebo-controlled phase 3 trial. The HRR-deficient cohort included randomly assigned patients from 142 hospitals, cancer centres, and medical centres in 26 countries; the study included men aged at least 18 years (≥20 years in Japan) with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer, progressive disease at study entry, and no previous life-prolonging systemic therapy for castration-resistant prostate cancer, but were receiving ongoing androgen deprivation therapy. Patients were prospectively assessed for tumour HRR gene alterations and randomly assigned (1:1) to once-daily oral talazoparib 0·5 mg plus enzalutamide 160 mg or enzalutamide plus placebo stratified by prior treatment (yes vs no) for castration-sensitive disease. The sponsor, patients, and investigators were masked to talazoparib or placebo, whereas enzalutamide was open label. The primary endpoint was rPFS (time from randomisation to radiographic progression or death, whichever occurred first) by blinded independent central review, and overall survival (time from randomisation to death due to any cause) was a key alpha-protected secondary endpoint, both assessed in the intention-to-treat population. Follow-up for overall survival was intended to continue until the planned final analysis. For statistical significance at the final overall survival analysis, the two-sided p value from the stratified log-rank test needed to be 0·024 or less based on a group sequential design with O'Brien–Fleming spending function. Safety was assessed in patients who had received at least one study drug dose. The trial is registered with ClinicalTrials.gov, NCT03395197. Between Dec 18, 2018, and Jan 20, 2022, 399 patients with HRR-deficient metastatic castration-resistant prostate cancer were randomly assigned (200 [50%] to talazoparib plus enzalutamide and 199 [50%] to enzalutamide plus placebo). At a median follow-up of 44·2 months (IQR 36·0–50·8), treatment with talazoparib plus enzalutamide resulted in a statistically significant improvement in overall survival versus enzalutamide (hazard ratio [HR] 0·62 [95% CI 0·48–0·81]; two-sided p=0·0005); median overall survival 45·1 months (95% CI 35·4–not reached) in the talazoparib group versus 31·1 months (27·3–35·4) in the control group. In the subgroup of patients with BRCA1/2 alterations (n=155 [39%]), median overall survival was not reached for talazoparib plus enzalutamide versus 28·5 months for enzalutamide (HR 0·50 [95% CI 0·32–0·78]; p=0·0017); 4-year overall survival rates were 53% in the talazoparib group versus 23% in the control group. In patients without BRCA1/2 alterations (n=244 [61%]), median overall survival was 42·4 months for talazoparib plus enzalutamide versus 32·6 months for enzalutamide (HR 0·73 [95% CI 0·52–1·02]; p=0·066). Updated rPFS favoured talazoparib plus enzalutamide versus enzalutamide (HR 0·47 [95% CI 0·36–0·61]; p<0·0001; median rPFS 30·7 vs 12·3 months). No new safety signals were identified; most common adverse events of grade 3 or higher with talazoparib plus enzalutamide were anaemia (86 [43%] patients) and neutropenia (39 [20%] patients). Talazoparib plus enzalutamide resulted in statistically significant and clinically meaningful improvement in survival versus enzalutamide plus placebo, further supporting this combination as a standard of care in HRR-deficient metastatic castration-resistant prostate cancer. Pfizer.