Docetaxel

Capivasertib combines with docetaxel to enhance anti-tumour activity through inhibition of AKT-mediated survival mechanisms in prostate cancer

Posted by

0


Abstract

Background/objective

To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null and WT prostate tumours.

Methods

Mechanisms associated with docetaxel capivasertib treatment activity in prostate cancer were examined using a panel of in vivo tumour models and cell lines.

Results

Combining docetaxel and capivasertib had increased activity in PTEN null and WT prostate tumour models in vivo. In vitro short-term docetaxel treatment caused cell cycle arrest in the majority of cells. However, a sub-population of docetaxel-persister cells did not undergo G2/M arrest but upregulated phosphorylation of PI3K/AKT pathway effectors GSK3β, p70S6K, 4E-BP1, but to a lesser extent AKT. In vivo acute docetaxel treatment induced p70S6K and 4E-BP1 phosphorylation. Treating PTEN null and WT docetaxel-persister cells with capivasertib reduced PI3K/AKT pathway activation and cell cycle progression. In vitro and in vivo it reduced proliferation and increased apoptosis or DNA damage though effects were more marked in PTEN null cells. Docetaxel-persister cells were partly reliant on GSK3β as a GSK3β inhibitor AZD2858 reversed capivasertib-induced apoptosis and DNA damage.

Conclusion

Capivasertib can enhance anti-tumour effects of docetaxel by targeting residual docetaxel-persister cells, independent of PTEN status, to induce apoptosis and DNA damage in part through GSK3β.

Discussion

Here, we show that combining the AKT inhibitor capivasertib with docetaxel increases anti-tumour effects in PTEN null and PTEN WT prostate tumour models and cell lines. In vivo the combination increased tumour growth inhibition in all models assessed, with significant tumour regressions in 3/6 models. In vitro sequential addition of capivasertib following short-term (24 h) docetaxel incubation reduced cell growth in PTEN null and WT cells. In vitro, acute docetaxel treatment killed a substantial number of cells and induced G2/M arrest. However, in a residual docetaxel-persister cell fraction that remained adherent to the plastic, a dose-dependent increase in phosphorylation of p70S6K, 4E-BP1 and in some cell lines, GSK3β occurred, which was reversed by capivasertib. These cells had progressed through G2/M arrest and remained in cycle without cell division. Generally, capivasertib monotherapy induces a G1/S arrest, and in combination capivasertib reduced cell cycle in docetaxel-persister cells. Moreover in 5/7 cell lines combination treatment increased apoptosis and induction of DNA damage. The fact that the increased apoptosis induced by capivasertib was reversed or reduced by inhibiting GSK3β suggests a direct role for AKT signalling. Although the PI3K/AKT inhibitor taxane combination is effective in preclinical models [1, 46, 47], PI3K-AKT pathway inhibition prior to taxane reduces efficacy as the PI3K-AKT mediated G1/S arrest blocks progression through S phase and G2 where taxanes induce cell death [26]. Inhibiting AKT post-taxane treatment increased tumour growth inhibition in breast, gastric and prostate cancer models [1, 25, 27, 29].

It has been suggested that long term resistance to docetaxel is associated with an increase in AKT phosphorylation [25, 30, 35]. Here in PTEN WT and PTEN null prostate cancer cells, following acute treatment with docetaxel the increased AKT phosphorylation in the docetaxel-persister cells was less apparent in the cell lines tested. Commonly phosphorylation of p70S6K(T421/S424) and 4E-BP1(T37/46), downstream of AKT, was observed. Induction of phospho-GSK3β (S9) was also observed with docetaxel treatment in some cell lines, while in cell lines where increased phosphorylation of GSK3β was less apparent baseline phospho-GSK3β levels were high prior to treatment. Interestingly increased phosphorylation of S6 was not seen in all cell lines, which may indicate that increased PI3K-AKT pathway activation in docetaxel-persister cells influences cell cycle or survival rather than general PI3K-mTOR activation including effects on protein synthesis [36, 48]. Modulation of 4E-BP1 also suggests a cell cycle or cell stress response following docetaxel treatment [37, 38]. One other study has examined the acute response to docetaxel in ER+ breast cancer MCF7 cells where a transient increase in pAKT was observed [49]. However, the induction of signalling downstream of AKT in the absence of increased pAKT signalling has been observed in other settings. In ER+ breast cancer cell lines that have become oestrogen independent following long term oestrogen deprivation, or resistant to the CDK4/6 inhibitor palbociclib increases in pS6 and other markers downstream of AKT are observed but little pAKT is detected or minimal to no change in pAKT [50, 51]. The significance of this warrants further investigation. While the data show persister cells are impacted by capivasertib treatment, we have not performed unbiased phospho-site profiling or reverse phase protein array phospho analysis to look at all changes following docetaxel and combination treatment, therefore changes in other proteins or pathways may be associated with survival of the docetaxel persister cells.

It was clear that across a panel of tumour cells the response to docetaxel and hence the combination was heterogeneous. In vitro combination activity was enhanced in cells with monotherapy sensitivity to capivasertib. However, in vivo additive anti-tumour combination effects were seen in 5 out of 6 models and appeared related to the intrinsic response of tumour models to docetaxel. In models that were more sensitive to docetaxel, capivasertib addition drove regressions, whereas in less sensitive models the combination resulted in cytostatic effects.

Inhibition of AKT signalling can contribute to combination benefit through different mechanisms, and it is possible that more than one mechanism is important in a specific cell line or tumour model. AKT-mediated phosphorylation of GSK3β, p70S6K and 4E-BP1, can enable evasion of apoptosis, cell cycle progression in the face of a G2/M blocker and absence of cell division. These mechanisms may not always be induced by docetaxel, cells may have higher baseline signalling, contributing to both intrinsic and induced resistance that is reduced by capivasertib treatment. For example, high intrinsic GSK3β activity could render docetaxel less effective independent of other PI3K pathway functions. While GSK3β may be an important mediator of persistence following docetaxel treatment, other mechanisms may also contribute, e.g. changes in translation downstream of mTORC1, coupling through 4E-BP1 or alternate non-canonical p70S6K signalling. For example, it is possible that intrinsic activity of AKT in the context of the cell cycle status of the persister cell fraction drives the survival effect. Alternatively pAKT increases may be more transient than the increase seen in GSK3β and p70S6K, but phosphorylation is still regulated by AKT or finally that docetaxel induced cell stress dysregulates phosphatases such as PTEN and PHLPP that control AKT [52, 53]. In addition TSC1, TSC2 [54], and PP2A [55] that regulate P70S6K could also be disrupted which may reduce the activation threshold for signalling molecules down stream of AKT. Indeed, in breast cancer cells reduction of mTORC1-4EBP1 signalling results in a reduction in PTEN protein [56]. It will be important to further evaluate whether other mechanisms that are regulated directly or indirectly by AKT modulation by capivasertib also make a contribution to the combination benefit. Variable sensitivity of prostate cancer cells to taxanes can also be influenced by differences in drug uptake and consequent intracellular levels of drug [57]. Therefore, different features may be important in different cells, and it is likely there is not one single unifying mechanism driving combination benefit. For example, it is possible that on long term treatment there may be engagement of the immune system, changes in the tumour microenvironment (TME) or adaptive responses in the TME, or the tumour cells.

Here, we have examined the acute interaction between docetaxel and capivasertib and sought to mimic the Phase II ProCAID study schedule [23, 24] in vivo and in vitro, but have not assessed prevention of longer-term resistance. The data presented here support the ProCAID study observation that the combination could be broadly effective in prostate cancer. How the pathway is activated remains an interesting question. It may be as a result of cells being in a specific phase of the cell cycle when treated with docetaxel, through inactivation of phosphatase regulation following redox stress, or signalling through other pathways such as activation of DNA damage repair proteins in response to aberrant mitosis [58].

In summary, combining the AKT inhibitor capivasertib with docetaxel in prostate cancer improves anti-tumour effects by targeting the residual surviving cells following docetaxel treatment. The benefit can be driven through different mechanisms downstream of AKT, by reducing AKT mediated cell cycle progression and enhancing induction of apoptosis or DNA damage in cells that persist after docetaxel treatment.

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS(G12C) mutation: a randomised, open-label, phase 3 trial.

Posted by

0


BACKGROUND: Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs.

METHODS: We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting.

FINDINGS: Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]).

INTERPRETATION: Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs.

Results of Phase III Randomized Trial for Use of Docetaxel as a Radiosensitizer in Patients With Head and Neck Cancer, Unsuitable for Cisplatin-Based Chemoradiation.

Posted by

0


PURPOSE: There is a lack of published literature on systemic therapeutic options in cisplatin-ineligible patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC) undergoing chemoradiation. Docetaxel was assessed as a radiosensitizer in this situation.

METHODS: This was a randomized phase II/III study. Adult patients (age = 18 years) with LAHNSCC planned for chemoradiation and an Eastern Cooperative Oncology Group performance status of 0-2 and who were cisplatin-ineligible were randomly assigned in 1:1 to either radiation alone or radiation with concurrent docetaxel 15 mg/m2 once weekly for a maximum of seven cycles. The primary end point was 2-year disease-free survival (DFS).

RESULTS: The study recruited 356 patients between July 2017 and May 2021. The 2-year DFS was 30.3% (95% CI, 23.6 to 37.4) versus 42% (95% CI, 34.6 to 49.2) in the RT and Docetaxel-RT arms, respectively (hazard ratio, 0.673; 95% CI, 0.521 to 0.868; P value = .002). The corresponding median overall survival (OS) was 15.3 months (95% CI, 13.1 to 22.0) and 25.5 months (95% CI, 17.6 to 32.5), respectively (log-rank P value = .035). The 2-year OS was 41.7% (95% CI, 34.1 to 49.1) versus 50.8% (95% CI, 43.1 to 58.1) in the RT and Docetaxel-RT arms, respectively (hazard ratio, 0.747; 95% CI, 0.569 to 0.980; P value = .035). There was a higher incidence of grade 3 or above mucositis (22.2% v 49.7%; P < .001), odynophagia (33.5% v 52.5%; P < .001), and dysphagia (33% v 49.7%; P = .002) with the addition of docetaxel.

CONCLUSION: The addition of docetaxel to radiation improved DFS and OS in cisplatin-ineligible patients with LAHNSCC.

Androgen Receptor Signaling Inhibitors in Addition to Docetaxel with Androgen Deprivation Therapy for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Meta-analysis.

Posted by

0


CONTEXT: Recent randomized controlled trials (RCTs) examined the role of adding androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalutamide, darolutamide (DAR), and enzalutamide (ENZ), to docetaxel (DOC) and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

OBJECTIVE: To analyze the oncologic benefit of triplet combination therapies using ARSI + DOC + ADT, and comparing them with available treatment regimens in patients with mHSPC.

EVIDENCE ACQUISITION: Three databases and meetings abstracts were queried in April 2022 for RCTs analyzing patients treated with first-line combination systemic therapy for mHSPC. The primary interests of measure were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were conducted to assess the differential outcomes in patients with low- and high-volume disease as well as de novo and metachronous metastasis.

EVIDENCE SYNTHESIS: Overall, 11 RCTs were included for meta-analyses and network meta-analyses (NMAs). We found that the triplet combinations outperformed DOC + ADT in terms of OS (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65-0.84) and PFS (pooled HR: 0.49, 95% CI: 0.42-0.58). There was no statistically significant difference between patients with low- and high-volume disease in terms of an OS benefit from adding an ARSI to DOC +ADT (both HR: 0.79; p = 1). Based on NMAs, triplet therapy also outperformed ARSI + ADT in terms of OS (DAR + DOC + ADT: pooled HR: 0.74, 95% CI: 0.55-0.99) and PFS (ABI + DOC + ADT: HR: 0.68, 95% CI: 0.51-0.91, and ENZ + DOC + ADT: HR: 0.70, 95% CI: 0.53-0.93). An analysis of treatment ranking among de novo mHSPC patients showed that triplet therapy had the highest likelihood of improved OS in patients with high-volume disease; however, doublet therapy using ARSI + ADT had the highest likelihood of improved OS in patients with low-volume disease.

CONCLUSIONS: We found that the triplet combination therapy improves survival endpoints in mHSPC patients compared with currently available doublet treatment regimens. Our findings need to be confirmed in further head-to-head trials with longer follow-up and among various patient populations.

PATIENT SUMMARY: Our study suggests that triplet therapy with androgen receptor signaling inhibitor, docetaxel, androgen deprivation therapy prolongs survival in patients with metastatic hormone-sensitive prostate cancer compared with the current standard doublet therapy.

Docetaxel for Prostate Cancer: ‘Win-Win-Win’

Posted by

0


Adding the chemotherapy docetaxel to standard hormone therapy for both metastatic and nonmetastatic prostate cancer is a win-win-win because it improves patients’ overall quality of life (QoL), reduces the need for subsequent therapy, and is cost-effective, according to a new modeling study from the investigators of a major clinical trial.

That trial, known as STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy), helped establish that docetaxel was an effective option in the treatment of metastatic prostate cancer (Lancet. 2016;387:1163-1177). The study showed a 10-month overall survival benefit when the drug was added to androgen deprivation therapy (ADT) for hormone-sensitive metastatic prostate cancer compared with ADT alone.

However, use of docetaxel in nonmetastatic disease has been considered controversial  because the difference in survival was not as pronounced in this earlier stage of disease as it was in metastatic disease and did not reach statistical significance, as reported at the time by Medscape Medical News.

Now, the lead author of STAMPEDE, Nicholas D. James, MD, PhD, professor of clinical oncology, University of Birmingham, United Kingdom, is championing the idea.

“Results suggest use of docetaxel in selected nonmetastatic patients should be considered,” he said in a presscast ahead of the Genitourinary Cancers Symposium (GUCS) 2018, which will be held later this week in San Francisco.

The triple benefit (QoL, less need for more therapy, cost-effectiveness) seen in nonmetastatic disease is “somewhat surprising and may cause clinicians to rethink how and when they use docetaxel to treat prostate cancer,” he said.

Dr James will be presenting results from the new modeling study, which  calculated lifetime predictions of costs, changes in predicted survival duration, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. The researchers used data on both men with metastatic (M1) and nonmetastatic (M0) disease, as the trial included both populations.

Health outcomes and costs in the UK National Health Service were modeled by using EuroQol (EQ-5D), which is a standardized self-reporting tool, and resource-use data collected within the STAMPEDE trial. In the trial, standard of care was ADT for at least 2 years and, in some patients, radiotherapy. Docetaxel (75 mg/m2) was administered alongside standard of care for six 3-weekly cycles with prednisolone 10 mg daily.

The team reported that docetaxel was estimated to extend predicted survival by an average of 0.89 years for M1 patients and 0.78 years for M0 patients, compared with patients receiving standard of care.

Docetaxel was also estimated to extend QALYs by 0.51 years in M1 patients and 0.39 years in M0 patients — and the findings for this measure had a “high degree of certainty,” Dr James commented. QALY gains in M0 patients were driven by the “beneficial effect of delayed and reduced relapse,” the authors said.

Compared with standard of care, docetaxel was cost-effective in both M1 patients and M0 patients. A sensitivity analysis indicated a “very high probability” (>99%) that docetaxel is cost-effective in both M0 and M1 patients, the authors also stated. Docetaxel remained cost-effective in M0 patients because of reductions and delays in relapse; this held true even when no survival advantage was assumed.

How Does This Compare to Abiraterone?

The new data prompted Sumanta K. Pal, MD, an American Society of Clinical Oncology (ASCO) expert and urologic oncologist at City of Hope, Duarte, California, and moderator of the GUCS presscast, to think about another drug used in this setting, abiraterone (Zytiga, Janssen).

“I will be interesting to assess these results [ie cost and QoL for docetaxel] against recent data for abiraterone, an oral hormonal therapy for prostate cancer, which has similar benefit in the same settings in prostate cancer,” he told reporters.

“Abiraterone may have the benefit of improved tolerability over a short course vs chemotherapy but does require a much more extensive duration of use and further mandates concomitant intake of prednisone, a steroid,” Dr Pal said.

Understanding the cost and quality of life associated with abiraterone may help in selecting either it or docetaxel for these patients with prostate cancer, he summarized.

Press materials from ASCO further pointed out that docetaxel is much less expensive: For the average patient with prostate cancer in the United Kingdom, a course of docetaxel costs £5000 (approximately $6000) per year, compared with £24,000 ($28,800) for abiraterone.

Seven-Month Prostate-Specific Antigen Is Prognostic in Metastatic Hormone Sensitive Prostate Cancer Treated With Androgen Deprivation With Or Without Docetaxel.

Posted by

0


Abstract

Purpose We evaluated the relationship between prostate-specific antigen (PSA) and overall survival in the context of a prospectively randomized clinical trial comparing androgen-deprivation therapy (ADT) plus docetaxel with ADT alone for initial metastatic hormone-sensitive prostate cancer. Methods We performed a landmark survival analysis at 7 months using the E3805 Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) database ( ClinicalTrials.gov identifier: NCT00309985). Inclusion required at least 7 months of follow-up and PSA levels at 7 months from ADT initiation. We used the prognostic classifiers identified in a previously reported trial (Southwest Oncology Group 9346) of PSA ≤ 0.2, > 0.2 to 4, and > 4 ng/dL. Results Seven hundred nineteen of 790 patients were eligible for this subanalysis; 358 were treated with ADT plus docetaxel, and 361 were treated with ADT alone. Median follow-up time was 23.1 months. On multivariable analysis, achieving a 7-month PSA ≤ 0.2 ng/dL was more likely with docetaxel, low-volume disease, prior local therapy, and lower baseline PSAs (all P ≤ .01). Across all patients, median overall survival was significantly longer if 7-month PSA reached ≤ 0.2 ng/dL compared with > 4 ng/dL (median survival, 60.4 v 22.2 months, respectively; P < .001). On multivariable analysis, 7-month PSA ≤ 0.2 and low volume disease were prognostic of longer overall survival (all P < 0.01). The addition of docetaxel increased the likelihood of achieving a PSA ≤ 0.2 ng/dL at 7 months (45.3% v 28.8% of patients on ADT alone). Patients on ADT alone who achieved a 7-month PSA ≤ 0.2 ng/dL had the best survival and were more likely to have low-volume disease (56.7%). Conclusion PSA ≤ 0.2 ng/dL at 7 months is prognostic for longer overall survival with ADT for metastatic hormone-sensitive prostate cancer irrespective of docetaxel administration. Adding docetaxel increased the likelihood of a lower PSA and improved survival.

Adding therapeutic vaccine to docetaxel ups PFS in metastatic breast cancer

Posted by

0


Adding the investigational therapeutic cancer vaccine PANVAC to docetaxel prolongs progression-free survival (PFS) in patients with metastatic breast cancer, a phase II study finds. [JAMA Oncol 2015, doi:10.1001/jamaoncol.2015.2736]

“Previous vaccine monotherapy trials have often failed to demonstrate improvements in short-term endpoints, such as PFS, despite improvements in long-term outcomes, such as overall survival. This may be explained by the lag between initial vaccination and eventual slowing of tumour growth rate,” wrote investigators of the study. “If this hypothesis is correct, then combining therapeutic cancer vaccines with standard-of-care agents may provide adequate time for the vaccines to take effect, resulting in improved PFS compared with the standard agents alone.”

In the study, 48 patients with metastatic breast cancer were randomized to receive docetaxel alone or in combination with PANVAC. Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoint of PFS, although not statistically significant, favoured the combination arm (median, 7.9 months vs 3.9 months in the docetaxel-alone arm; hazard ratio, 0.65; p=0.09). “The statistical insignificance was likely owing to the small number of patients enrolled in this study,” the investigators noted.

Partial response was achieved in 16 percent of patients in the combination arm and 13 percent of patients in the docetaxel-alone arm.

The overall safety profile was comparable between the two arms, with the exception of significantly higher rates of injection site reactions (64 vs 0 percent; p<0.001) and oedema (44 vs 13 percent; p=0.02) in patients receiving PANVAC plus docetaxel. The investigators added, however, that the higher incidence of oedema observed in the combination arm was primarily due to the longer exposure to docetaxel as a result of prolonged PFS.

“We demonstrated that PANVAC can be safely combined with docetaxel to benefit patients with metastatic breast cancer,” they concluded. “These findings provide both a rationale and statistical assumptions for a larger definitive randomized study in a more uniform patient population.”

Patients who received PANVAC in this study were first given the priming vaccine PANVAC-V, followed by the monthly boosting vaccine PANVAC-F. With every vaccination, they also received an injection of granulocyte-macrophage colony-stimulating factor to boost the immune system.

Drug for Advanced Prostate Cancer Approved.

Posted by

0


The Food and Drug Administration (FDA) has approved enzalutamide (Xtandi) to treat men with advanced prostate cancer that has spread or recurred after medical or surgical therapy to minimize testosterone, which fuels tumor growth. The drug was approved for use in prostate cancer patients previously treated with docetaxel.

The safety and effectiveness of enzalutamide—previously called MDV3100—was evaluated in a study of 1,199 patients with metastatic castration-resistant prostate cancer who had received prior treatment with docetaxel. The median overall survival for patients who received enzalutamide was 18.4 months, compared with 13.6 months for those who received a placebo.

The most common side effects were fatigue, back pain, diarrhea, joint pain, hot flush, tissue swelling, musculoskeletal pain, respiratory infections, dizziness, spinal cord compression, blood in urine, tingling sensation, anxiety, and high blood pressure.

Seizures occurred in about 1 percent of those receiving enzalutamide. Study participants who had a seizure stopped enzalutamide therapy. The clinical study excluded men who had a history of seizure or several other brain conditions or who were taking medications that may cause seizures. The safety of enzalutamide in patients with these conditions is unknown.

Enzalutamide was reviewed under the FDA’s priority review program, which allows an expedited 6-month review for drugs that may offer major advances in treatment or that provide a treatment when no adequate therapy exists.

Source: NCI