Talzenna (talazoparib)

We suggest that talazoparib in combination with enzalutamide is probably a preferred treatment agent for the overall population and HRRm patients with mCRPC. Given the limitations of network framework and the modeling assumptions undertaken to finalize the analyses, results should be cautiously interpreted.

We clarified the patient's challenging diagnosis and discussed the clinicopathology, immunophenotype, differential diagnosis, and molecular genetic information regarding TFEB/6p21/VEGFA-amplified RCC via exome analysis and a literature review.

P1, N=24, Active, not recruiting, Roswell Park Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Oct 2025 --> Apr 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

P1, N=24, Recruiting, Fox Chase Cancer Center | Not yet recruiting --> Recruiting

P2, N=115, Terminated, Zenith Epigenetics | Trial completion date: Dec 2024 --> Mar 2024 | Active, not recruiting --> Terminated; Parts 1 and 2 and Expansion Cohort C were completed. Expansion Cohorts A and B were discontinued based on results from an interim futility analysis and not due to safety concerns.

P1/2, N=16, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=44 --> 16

Curcumin alone led to dose-dependent responses and when combined with BYL719, positive effects were revealed, as they were when it was combined with MK-1775 or PD-0332991, suggesting a potential use of some of these combinations for HPV+ OPSCC.

P1, N=35, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Phase classification: P1a/1b --> P1

P1/2, N=24, Active, not recruiting, Georgetown University | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024

Upregulation of intracellular NAD+ levels by the addition of nicotinamide also induced resistance to olaparib and talazoparib in C1 cells. Taken together, our findings suggest that upregulation of intracellular NAD+ is one of the factors underlying the acquisition of PARP inhibitor resistance.

Here, we review the newly approved PARPi plus ARSI treatments within the context of the mCRPC treatment landscape, provide an overview of practical considerations for the combinations in clinical practice, highlight the importance of HRR testing, and discuss the benefits of treatment intensification for patients with mCRPC.

Network meta-analysis results showed that cisplatin combined with nab-paclitaxel or paclitaxel was superior to docetaxel plus capecitabine in terms of PFS and ORR. For PD-L1 and BRCA mutation-positive tumors, atezolizumab/pembrolizumab combined with nab-paclitaxel and talazoparib is an effective treatment option. Neutropenia, diarrhea, and fatigue are frequently occurring serious adverse events.

P1/2, N=54, Not yet recruiting, German Cancer Research Center | Trial completion date: Jun 2027 --> Jun 2028 | Trial primary completion date: Jun 2027 --> Jun 2028

P3, N=61, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=262 --> 61 | Trial completion date: May 2025 --> Sep 2026 | Trial primary completion date: May 2025 --> Sep 2026

P1/2, N=75, Recruiting, Massachusetts General Hospital | Phase classification: P1b/2 --> P1/2 | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2025

P1, N=25, Recruiting, Roswell Park Cancer Institute | Active, not recruiting --> Recruiting

P1, N=34, Completed, Kathy Miller | Recruiting --> Completed | Trial completion date: Jul 2025 --> Mar 2024 | Trial primary completion date: Dec 2024 --> Jan 2024

P2, N=30, Recruiting, Massachusetts General Hospital | Trial completion date: Jul 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Jul 2025

As single agent, M1774 suppressed cancer cell viability at nanomolar concentrations, showing greater activity than ceralasertib and berzosertib, but less potency than gartisertib and elimusertib in the small-cell lung cancer H146, H82, and DMS114 cell lines. Low dose of M1774 was found highly synergistic with a broad spectrum of clinical DDAs including TOP1 inhibitors (SN-38/irinotecan, topotecan, exatecan, and exatecan), the TOP2 inhibitor etoposide, cisplatin, the RNA polymerase II inhibitor lurbinectedin, and the PARP inhibitor talazoparib in various models including cancer cell lines, patient-derived organoids, and mouse xenograft models. Furthermore, we demonstrate that M1774 reverses chemoresistance to anticancer DDAs in cancer cells lacking SLFN11 expression, suggesting that SLFN11 can be utilized for patient selection in upcoming clinical trials.

Despite a statistically significant rPFS improvement in the all-comer cohort, FDA did not consider the magnitude of rPFS clinically meaningful in the context of the broad indication, combination treatment, and safety profile. Approval was therefore limited to patients with HRRm mCRPC, for whom there was a statistically significant and clinically meaningful improvement in rPFS and favorable OS results. This represents the first approval for the first-line treatment of patients with HRRm mCRPC.

TALA + ENZA improved outcomes compared with PBO + ENZA in patients with muts in specific non-HRR genes (regardless of HRR gene muts). TMPRSS2-ERG and RB1 emerged as candidate predictive biomarkers for differential efficacy favoring TALA + ENZA vs PBO + ENZA. PARP inhibitors may induce a synthetically lethal interaction with TMPRSS2-ERG-mediated inhibition of non-homologous end joining and help overcome RB1-mediated ENZA resistance.

Our exploratory analysis identified candidate gene expression signatures, including AR pathway elements, potentially associated with differential benefit from TALA + ENZA, reinforcing the potential for exploitable crosstalk between AR and DNA repair pathways. Though validation is necessary, a predictive multiomic signature for benefit from TALA + ENZA regardless of HRR alteration status was identified that included alterations in genes previously implicated in prognosis and expression of multiple AR target transcripts. Strikingly, it did not include any of the 12 HRR genes used in prospective stratification for TP-2, reinforcing the potential benefit for TALA + ENZA beyond HRR-deficient tumors.

P2, N=30, Not yet recruiting, M.D. Anderson Cancer Center | Initiation date: Sep 2023 --> Sep 2024

Since the approval of olaparib and talazoparib for advanced human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer, several phase IIIb-IV trials, expanded access cohorts, and retrospective cohorts have provided information on the efficacy and tolerability of these treatments in patient subgroups underrepresented in the registration trials, such as older adults, patients with poor performance status, and heavily pretreated patients. The aim of this review is to present a critical review of the information regarding the use of PARPi in real-world breast cancer patients.

Notably, there was a high proportion of patients with visceral progression even with visceral crisis and need for CT. Interestingly, there were similar rwOS results among subgroups (TNBC versus ER + ve/HER2-ve, talazoparib versus olaparib, etc).

Based on the PROfound and TRITON3 trials, olaparib and rucaparib were respectively approved as monotherapy in pretreated patients with mCRPC and alterations in prespecified genes. The combinations of olaparib with abiraterone (PROpel) and niraparib with abiraterone (MAGNITUDE) were approved as first-line options in patients with mCRPC and alterations in BRCA1/2, whereas the combination of talazoparib with enzalutamide (TALAPRO-2) was approved in the same setting in patients with alterations in any of the HRR genes, which are found in around a quarter of patients with advanced prostate cancer...Future directions will include refining the treatment sequencing in patients with mCRPC in the clinic while taking into account the financial toxicity as well as the potential side effects encountered with these therapies and elucidating their mechanism of action in patients with non-altered HRR genes. Herein, we review the biological rationale behind using PARPis in mCRPC and the key aforementioned clinical trials that paved the way for these approvals.

P2, N=54, Active, not recruiting, MedSIR | Recruiting --> Active, not recruiting

P3, N=262, Recruiting, Pfizer | Trial completion date: Dec 2025 --> May 2025 | Trial primary completion date: Dec 2025 --> May 2025

P1/2, N=37, Active, not recruiting, Kari Wisinski | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024

The identification of genomic loss of heterozygosity as a biomarker targets HRR-deficient cancers, enhancing talazoparib's efficacy. These breakthroughs represent a significant advancement in precision medicine, offering more effective, individualized cancer therapies.

The therapeutic efficacy of talazoparib in cancer may be compromised by its susceptibility to MDR, which is attributed to its interactions with the ABCC1 or ABCG2 transporters. The overexpression of these transporters can potentially diminish the therapeutic impact of talazoparib in cancer treatment.

Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression...H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.

P2, N=115, Active, not recruiting, Zenith Epigenetics | Recruiting --> Active, not recruiting

"Chugai Pharmaceutical...announced that it has obtained approval from the Ministry of Health, Labour and Welfare (MHLW) on February 2, 2024, for FoundationOne CDx Cancer Genomic Profile to be used as a companion diagnostic for...TALZENNA capsules...which is approved for BRCA gene mutation-positive castration-resistant prostate cancer with distant metastases....This approval enables the detection of BRCA1/2 gene mutations using the FoundationOne CDx Cancer Genome Profile to assist of the decision to use talazoparib for BRCA gene mutation-positive castration-resistant prostate cancer with distant metastases. The efficacy and safety of combination therapy of talazoparib and enzalutamide for BRCA gene mutation-positive castration-resistant prostate cancer with distant metastases was evaluated in the global phase III study TALAPRO-2. Pfizer Japan Inc. obtained approval from the MHLW on January 18th, 2024."

Approximately, 30% of recurrent EC pts fall into this category. Pairing ICI with targeted therapies carries the potential to elicit prolonged anti-tumor effects. Atezolizumab (Atezo) is a humanized monoclonal PD-L1 inhibitor that has demonstrated monotherapy antitumor activity with an acceptable safety profile in relapsed recurrent EC...In cohort A, pts may be eligible for one of the following doublets: Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered cancers), Atezo+talazoparib (tumors with genomic loss of heterozygosity (LOH) ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated and/or amplified tumors), and Atezo+Tiragolumab (MSI-H and/or TMB>10 mut/MB). The Atezo+bevacizumab (biomarker unmatched) arm is closed to enrollment...Pts will receive Atezo in addition to the targeted agent (at the study approved dosing schedule) until progression, unacceptable toxicity, pt or physician decision to withdraw from the study, death, or study termination. Pts in cohort B, will be eligible for inavolisib (PIK3CA/PTEN/AKT1-altered cancers) + letrozole. The primary endpoint for Cohort A is confirmed overall response rate (ORR) for each cohort, and for Cohort B is progression free survival at 6 months...As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 18 sites in the US with a target of 25 sites nationwide.

The aim of the present systematic review and meta-analysis is to evaluate the efficacy and safety of approved (Olaparib, Rucaparib) and investigational (Talazoparib, Niraparib, Veliparib) PARPi in mCRPC patients. PARP inhibitors represent a viable option for mCRPC patients. Current evidence suggests an increased effectiveness in homologous recombination repair (HRR) gene mutation carriers, especially BRCA2.

P1, N=24, Not yet recruiting, Fox Chase Cancer Center

P3, N=1054, Active, not recruiting, Pfizer | Trial completion date: Jul 2024 --> Dec 2025

P1, N=25, Recruiting, University of Michigan Rogel Cancer Center | Trial completion date: Dec 2023 --> Jul 2024 | Trial primary completion date: Dec 2023 --> Jul 2024

To expand the benefit of PARPi to patients without detectable HRR alterations, multiple studies are addressing potential synergies between PARP inhibition (PARPi) and androgen receptor pathway inhibitors (ARSi), radiation, radioligand therapy, chemotherapy, or immunotherapy, and these strategies are also being evaluated in the hormone-sensitive setting. In this review, we summarize the development of PARPi in prostate cancer, the potential synergies, and combinations being investigated as well as the future directions of PARPi for the management of the disease.

Moreover, breast cancer tissue microarrays (TMAs) showed a positive correlation between stable p53 and high PARP1 expression in sub-groups of breast cancers, which may indicate sub-classes of breast cancers sensitive to PARPi therapy. These results suggest that mtp53 could be a biomarker to predict response to the combination of PARPi talazoparib-temozolomide treatment.

Moreover, we further analyzed the 46/talazoparib combination in 3D pancreatic cancer models. Overall, 46 showed its potential as a tool to evaluate the RAD51/PARP1-2 synthetic lethality mechanism, along with providing a prospect for further inhibitors development.