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The Demise of Chemotherapy in Front-Line mCRPC?

In recent years the field of prostate cancer has undergone significant evolution with the introduction of newer, better-tolerated treatment options. The introduction of the first therapeutic cancer vaccine (Provenge, Dendreon) sparked the idea of treating metastatic castrate-resistant prostate cancer (mCRPC) patients who weren’t symptomatic. This was followed by the advent of novel hormonal therapies being used in the post-chemotherapy setting, which challenged the previous notion that these patients were hormone-insensitive. Most recently, we’re witnessing the influx of these novel hormonal therapies into the pre-chemotherapy setting. However, one area that has remained stable over the years is the treatment paradigm for newly symptomatic mCRPC. The TAX327 trial was key in establishing docetaxel plus prednisone as the “gold standard” for patients with mCRPC. For nearly a decade it’s been a foregone conclusion that docetaxel is the best treatment option for these patients, and to improve upon outcomes in the first-line setting we need to develop new regimens that build on the docetaxel foundation. In the era of targeted therapy, it’s not surprising that several targeted agents have been investigated to explore additive benefits to this regimen with the goal of improving survival beyond the 19 months that the docetaxel/prednisone regimen offers (Tannock, 2004). However, it is saddening to observe that front-line mCRPC has become a graveyard for novel therapies, including atrasentan (AstraZeneca), Avastin® (bevacizumab, Roche/Genentech/Chugai), Revlimid® (lenalidomide, Celgene), Zaltrap® (ziv-aflibercept, Regeneron/Sanofi), and zibotentan (ZD4054, AstraZeneca). Each of these drugs demonstrated early promise of activity, but each has attempted and failed to improve upon the bar that docetaxel set for overall survival. Now one more promising targeted agent has met with the same fate: Sprycel® (dasatinib, Bristol-Myers Squibb). The results from the pivotal READY trial were reported Thursday at the American Society of Clinical Oncology (ASCO) Genitourinary Cancer Symposium in Orlando, Florida.

The trial (NCT00744497) evaluated whether Sprycel improved survival when added to the docetaxel/prednisone regimen as first-line therapy in mCRPC patients. The study accrued 1,522 patients who were randomized 1:1 to Sprycel/docetaxel/prednisone or docetaxel/prednisone. Disappointingly, the study failed to achieve an improvement in median overall survival (mOS): the curves for the two arms were overlapping (mOS 21.2 months in placebo/docetaxel arm versus 21.5 months in Sprycel/docetaxel/prednisone arm; HR 0.99, p=0.9009). Subset analysis by age, EGOG status, bone metastasis or PSA progression also failed to demonstrate any difference in mOS between the two arms. There was no difference in median progression-free survival (mPFS) in the Sprycel/docetaxel/prednisone arm versus placebo/docetaxel/prednisone arm (11.8 versus 11.1 months; HR 0.92, p=0.2164). A modest delay in skeletal-related events was observed in the Sprycel arm, which was not entirely surprising considering the Src relation to osteoclasts.

The efficacy of placebo/docetaxel/prednisone arm in the READY trial is strikingly similar to that observed in the placebo/docetaxel/prednisone arm from the Zaltrap pivotal trial (VENICE) (Tannock, Abstract 13, ASCO GI 2013). The VENICE trial was previously reported to have failed via press release, but this was the first time that complete data was reported. In the VENICE trial, Zaltrap plus docetaxel/prednisone achieved a mOS of 22.1 months, which was not significantly different (p=0.38) compared to 21.2 months mOS in the placebo/docetaxel/prednisone arms. There were no differences in mPFS or PSA responses between the Zaltrap/docetaxel/prednisone and placebo/docetaxel/prednisone arms (mPFS: 6.9 versus 6.2 months; PSA: 68.6% versus 63.5%). Additionally, Zaltrap added some toxicities, including gastrointestinal perforations, hypertension, infections and respiratory disorders, that led to shorter duration of treatment.

Mechanistically (Src kinase inhibition) and preclinical studies (synergism with docetaxel) laid a very solid foundation for the investigation of Sprycel in prostate cancer. However, the transition for Sprycel into clinics was based on mediocre Phase I/II results. In that study, the addition of Sprycel to docetaxel demonstrated an improvement in partial tumor response (60%) and superior PSA decline (57%) when compared with historical controls (Araujo, Cancer 2012, 118: 63-21). The biggest criticism of the READY trial was launch of a large, 1,500-patient Phase III trial on the basis of efficacy observed in a single-arm (less than 50 patients) Phase II study with no clear PFS or survival benefit. The caveats of comparing single-arm studies with historical data becomes more apparent when comparing the differences in OS benefit of the control arms in the READY and VENICE pivotal trials (mOS: 21.2 months) with that observed in the TAX327 trial (mOS: 19.2 months).

Is there any hope left for targeted therapies or novel chemotherapies hoping to improve upon the activity of docetaxel in first-line mCRPC? A quick review of history (eight failed agents) and current landscape (two in pivotal trials) might suggest “Very Slim.” Currently two agents are in pivotal clinical trials for chemotherapy-naïve symptomatic mCRPC. Custirsen (OGX-011, Oncogenex/Teva) is an antisense oligonucleotide that is currently in a Phase III trial (SYNERGY) in combination with docetaxel/prednisone versus docetaxel/prednisone. The primary endpoint is OS, and the trial is expected to report results by the end of 2013. The pivotal trial was initiated based on data from a randomized Phase II trial in which custirsen/docetaxel/prednisone failed to achieve the primary endpoint of improved PSA decline rate or improved response rate. However, custirsen/docetaxel/prednisone improved OS (23.8 months versus 16.9 months), and a trend to improved PFS was observed (7.3 versus 6.1 months) compared to docetaxel/prednisone. With the caveat of cross-trial comparison, the efficacy of the placebo arm in this Phase II trial compares closely to that from TAK327 trial but is much lower than that observed with docetaxel-alone arms in the VENICE and READY trials, leading to some concerns that SYNERGY could meet with the same fate.

The other agent in a pivotal trial in this setting is Jevtana® (cabazitaxel, Sanofi), which is a taxane derivative that is currently approved for docetaxel-pretreated mCRPC patients. Jevtana is being investigated in the Phase III FIRSTANA trial, comparing docetaxel plus prednisone versus Jevtana plus prednisone in first-line mCRPC. The endpoint of this trial is OS, and the trial will report by the end of 2013. To date, Jevtana has not been explored in a head-to-head trial with docetaxel, and the only available results are from docetaxel-refractory patients, where Jevtana/prednisone achieved mOS of 15.1 months and mPFS of 2.8 months (deBono, Lancet 2010; 1147-1154). It would be interesting to see whether Jevtana will be able to demonstrate superiority to docetaxel in the front-line setting and manage to maintain a decent toxicity profile with few discontinuations due to toxicity.

The mCRPC market appears to be on a trajectory toward a relinquishment to novel hormonal agents and a regression of chemotherapy and other targeted therapies to later lines. If Jevtana manages to supersede docetaxel, it may only be a marginal improvement in this field, with a swap of one taxane for another. As the only targeted agent left in late-stage development seeking to improve upon the efficacy of docetaxel, custirsen could be the only hope left to rejuvenate interest in targeted therapy plus chemotherapy combinations, keeping alive the complex interplay between hormones and chemotherapy in the management of mCRPC.

By: Neesha Suvarna, PhD, Consultant, Kantar Health

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