Clinical trials studying neoadjuvant and adjuvant therapy around prostatectomy for patients with high‐risk prostate cancer have faced multiple challenges. Patients who have a very good response to ...neoadjuvant therapy may not wish to continue to adjuvant treatment, and prostate‐specific antigen–based end points are difficult to interpret because of variations in testosterone recovery.
Targeting TMPRSS2 in SARS-CoV-2 Infection Baughn, Linda B; Sharma, Neeraj; Elhaik, Eran ...
Mayo Clinic proceedings,
09/2020, Letnik:
95, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has rapidly caused a global pandemic associated with a novel respiratory infection: coronavirus disease-19 (COVID-19). ...Angiotensin-converting enzyme-2 (ACE2) is necessary to facilitate SARS-CoV-2 infection, but-owing to its essential metabolic roles-it may be difficult to target it in therapies. Transmembrane protease serine 2 (TMPRSS2), which interacts with ACE2, may be a better candidate for targeted therapies. Using publicly available expression data, we show that both ACE2 and TMPRSS2 are expressed in many host tissues, including lung. The highest expression of ACE2 is found in the testes, whereas the prostate displays the highest expression of TMPRSS2. Given the increased severity of disease among older men with SARS-CoV-2 infection, we address the potential roles of ACE2 and TMPRSS2 in their contribution to the sex differences in severity of disease. We show that expression levels of ACE2 and TMPRSS2 are overall comparable between men and women in multiple tissues, suggesting that differences in the expression levels of TMPRSS2 and ACE2 in the lung and other non-sex-specific tissues may not explain the gender disparities in severity of SARS CoV-2. However, given their instrumental roles for SARS-CoV-2 infection and their pleiotropic expression, targeting the activity and expression levels of TMPRSS2 is a rational approach to treat COVID-19.
Genomic alterations in DNA damage repair (DDR) genes other than
may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this ...hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-
DDR gene alterations.
TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline).
TRITON2 enrolled 78 patients with a non-
DDR gene alteration
(
= 49),
(
= 15),
(
= 12), and other DDR genes (
= 14). Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in
2/19 (10.5%) and 2/49 (4.1%), respectively,
0/10 (0%) and 1/15 (6.7%), respectively, or
1/9 (11.1%) and 2/12 (16.7%), respectively, including no radiographic or PSA responses in 11 patients with confirmed biallelic
loss or 11 patients with
germline mutations. Responses were observed in patients with alterations in the DDR genes
, and
.
In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in
, or
. However, patients with alterations in other DDR-associated genes (e.g.,
) may benefit from PARP inhibition.
.
or
(
) alterations are common in men with metastatic castration-resistant prostate cancer (mCRPC) and may confer sensitivity to poly(ADP-ribose) polymerase inhibitors. We present results from ...patients with mCRPC associated with a
alteration treated with rucaparib 600 mg twice daily in the phase II TRITON2 study.
We enrolled patients who progressed after one to two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Efficacy and safety populations included patients with a deleterious
alteration who received ≥ 1 dose of rucaparib. Key efficacy end points were objective response rate (ORR; per RECIST/Prostate Cancer Clinical Trials Working Group 3 in patients with measurable disease as assessed by blinded, independent radiology review and by investigators) and locally assessed prostate-specific antigen (PSA) response (≥ 50% decrease from baseline) rate.
Efficacy and safety populations included 115 patients with a
alteration with or without measurable disease. Confirmed ORRs per independent radiology review and investigator assessment were 43.5% (95% CI, 31.0% to 56.7%; 27 of 62 patients) and 50.8% (95% CI, 38.1% to 63.4%; 33 of 65 patients), respectively. The confirmed PSA response rate was 54.8% (95% CI, 45.2% to 64.1%; 63 of 115 patients). ORRs were similar for patients with a germline or somatic
alteration and for patients with a
or
alteration, while a higher PSA response rate was observed in patients with a
alteration. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (25.2%; 29 of 115 patients).
Rucaparib has antitumor activity in patients with mCRPC and a deleterious
alteration, but with a manageable safety profile consistent with that reported in other solid tumor types.
In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with ...a deleterious
alteration. Data are needed to confirm and expand on the findings of the phase 2 study.
In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a
,
, or
alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI abiraterone acetate or enzalutamide). The primary outcome was the median duration of imaging-based progression-free survival according to independent review.
Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a
alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval CI, 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea.
The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a
alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).
Recent data have revealed antitumor activity for four PARP inhibitors, two of which (olaparib and rucaparib) are approved by the US Food and Drug Administration for metastatic castrate-resistant ...prostate cancer with selected DNA repair defects. Additional clinical trials are in progress for talazoparib, veliparib, and niraparib. More progress can be anticipated in the near future.
Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, are being explored as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) in men harboring mutations in ...homologous recombination DNA-repair genes. Whether responses to PARP inhibitors differ according to the affected gene is currently unknown.
To determine whether responses to PARP inhibitors differ between men with BRCA1/2 and those with ATM mutations.
This was a multicenter retrospective review of 23 consecutive men with mCRPC and pathogenic germline and/or somatic BRCA1/2 or ATM mutations treated with olaparib at three academic sites in the USA.
The proportion of patients achieving a ≥50% decline in prostate-specific antigen (PSA50 response) was compared using Fisher's exact test. Clinical and radiographic progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier analyses and compared using the log-rank test.
The study included two men with BRCA1 mutations, 15 with BRCA2 mutations, and six with ATM mutations. PSA50 responses to olaparib were achieved in 76% (13/17) of men with BRCA1/2 versus 0% (0/6) of men with ATM mutations (Fisher's exact test; p=0.002). Patients with BRCA1/2 mutations had median PFS of 12.3mo versus 2.4mo for those with ATM mutations (hazard ratio 0.17, 95% confidence interval 0.05–0.57; p=0.004). Limitations include the retrospective design and relatively small sample size.
Men with mCRPC harboring ATM mutations experienced inferior outcomes to PARP inhibitor therapy compared to those harboring BRCA1/2 mutations. Alternative therapies should be explored for patients with ATM mutations.
Mutations in BRCA1/2 and ATM genes are common in metastatic prostate cancer. In this study we compared outcomes for men with BRCA1/2 mutations to those for men with ATM mutations being treated with olaparib. We found that men with ATM mutations do not respond as well as men with BRCA1/2 mutations.
In this retrospective review of 23 patients with BRCA1/2 or ATM mutations treated with olaparib, we found that none of six men with ATM mutations achieved a 50% decline in prostate-specific antigen, compared to 13/17 men with BRCA1/2 mutations. Patients with BRCA1/2 mutations also had longer progression-free survival on olaparib treatment. Men with metastatic castration-resistant prostate cancer harboring ATM mutations may not respond to PARP inhibitors as well as men with BRCA1/2 mutations and may require alternative therapies.
Identifying the most effective first-line treatment for metastatic renal cell carcinoma (mRCC) is challenging as rapidly evolving data quickly outdate the existing body of evidence, and current ...approaches to presenting the evidence in user-friendly formats are fraught with limitations.
To maintain living evidence for contemporary first-line treatment for previously untreated mRCC.
We have created a living, interactive systematic review (LISR) and network meta-analysis for first-line treatment of mRCC using data from randomized controlled trials comparing contemporary treatment options with single-agent tyrosine kinase inhibitors. We applied an advanced programming and artificial intelligence–assisted framework for evidence synthesis to create a living search strategy, facilitate screening and data extraction using a graphical user interface, automate the frequentist network meta-analysis, and display results in an interactive manner.
As of October 22, 2020, the LISR includes data from 14 clinical trials. Baseline characteristics are summarized in an interactive table. The cabozantinib + nivolumab combination (CaboNivo) is ranked the highest for the overall response rate, progression-free survival, and overall survival, whereas ipilimumab + nivolumab (NivoIpi) is ranked the highest for achieving a complete response (CR). NivoIpi, and atezolizumab + bevacizumab (AteBev) were ranked highest (lowest toxicity) and CaboNivo ranked lowest for treatment-related adverse events (AEs). Network meta-analysis results are summarized as interactive tables and plots, GRADE summary-of-findings tables, and evidence maps.
This innovative living and interactive review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated mRCC. Trial-level comparisons suggest that CaboNivo is likely to cause more AEs but is ranked best for all efficacy outcomes, except NivoIpi offers the best chance of CR. Pembrolizumab + axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk. Although network meta-analysis provides rankings with statistical adjustments, there are inherent biases in cross-trial comparisons with sparse direct evidence that does not replace randomized comparisons.
It is challenging to decide the best option among the several treatment combinations of immunotherapy and targeted treatments for newly diagnosed metastatic kidney cancer. We have created interactive evidence summaries of multiple treatment options that present the benefits and harms and evidence certainty for patient-important outcomes. This evidence is updated as soon as new studies are published.
This innovative living and interactive systematic review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated metastatic renal cell carcinoma. The cabozantinib + nivolumab combination is likely to cause more adverse events but is ranked best for all efficacy outcomes, except for ipilimumab in combination with nivolumab (NivoIpi), which offers the best chance of a complete response. Pembrolizumab-axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk.
Relapsing level of prostate-specific antigen (PSA) after initial curative-intent local therapy for organ-confined prostate cancer is often the first sign of recurrence. However, PSA level recurrence ...does not enable accurate differentiation of locally recurrent tumor from metastatic disease or a combination of both. Metastatic prostate cancer most frequently involves bones and lymph nodes, followed by other organs such as the liver, lung, pleura, adrenal gland, ureter, peritoneum, penis, testis, and meninges. Conventional imaging including CT and bone scintigraphy has long been the standard of care but has limited sensitivity in depicting early local recurrence or metastatic disease. Multiparametric MRI has been shown to be more sensitive in detecting locally recurrent tumor in the prostatectomy bed as well as in situ recurrence in a prostate gland that has been treated with radiation therapy or thermal ablation. In addition, lesions detected with multiparametric MRI may be amenable to targeted biopsy for definitive diagnosis of recurrence. PET/CT or PET/MRI using the U.S. Food and Drug Administration (FDA)-approved tracers carbon 11 choline or fluorine 18 fluciclovine has demonstrated markedly increased sensitivity and specificity for diagnosis of early metastatic disease such as small-volume lymph node metastasis, as have a range of investigational gallium 68 prostate-specific membrane antigen (PSMA) radioactive PET tracers. With recent advances in imaging modalities and techniques, more accurate early detection, localization, and characterization of recurrent prostate cancer have become possible. The authors present a contemporary review of the strengths and limitations of conventional and advanced imaging modalities in evaluation of patients with recurrent prostate cancer and a systematic review of the clinical and imaging features of locally recurrent and metastatic disease.
RSNA, 2020See discussion on this article by Barwick and Castellucci.
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